N-Substituted Benzene Sulfonamides

ABSTRACT

Disclosed are N-substituted benzenesulfonamides for use in treating or preventing cognitive disorders, such as Alzheimer&#39;s Disease. 
     
       
         
         
             
             
         
       
     
     In Formula (I), R 1 , R 2 , R 3 , R 4 , R 3′ , R 10  and R 11  are as described herein. The invention also encompasses pharmaceutical compositions comprising compounds of Formula (I) as well as methods of treating cognitive disorders using compounds of Formula (I).

This application claims priority from U.S. provisional patent application No. 60/515,612, filed Oct. 29, 2003.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to N-substituted benzene sulfonamides which inhibit β-amyloid peptide release and/or its synthesis and, therefore, are useful in the prevention of cognitive disorders in patients susceptible to cognitive disorders and/or in the treatment of patients with cognitive disorders in order to inhibit further deterioration in their condition.

2. State of the Art

Alzheimer's Disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and ultimately death. AD is a very common cause of progressive mental failure (dementia) in aged humans and is believed to represent the fourth most common medical cause of death in the United States. AD has been observed in races and ethnic groups worldwide and presents a major present and future public health problem. The disease is currently estimated to affect about two to three million individuals in the United States alone. AD is at present incurable. No treatment that effectively prevents AD or reverses its symptoms and course is currently known.

The brains of individuals with AD exhibit characteristic lesions termed senile (or amyloid) plaques, amyloid angiopathy (amyloid deposits in blood vessels) and neurofibrillary tangles. Large numbers of these lesions, particularly amyloid plaques and neurofibrillary tangles, are generally found in several areas of the human brain important for memory and cognitive function in patients with AD. Smaller numbers of these lesions in a more restrictive anatomical distribution are also found in the brains of most aged humans who do not have clinical AD. Amyloid plaques and amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down's Syndrome) and Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D). At present, a definitive diagnosis of AD usually requires observing the aforementioned lesions in the brain tissue of patients who have died with the disease or, rarely, in small biopsied samples of brain tissue taken during an invasive neurosurgical procedure.

The principal chemical constituent of the amyloid plaques and vascular amyloid deposits (amyloid angiopathy) characteristic of AD and the other disorders mentioned above is an approximately 4.2 kilodalton (kD) protein of about 39-43 amino acids designated the β-amyloid peptide (βAP) or sometimes Aβ, AβP or β/A4. β-Amyloid peptide was first purified and a partial amino acid sequence was provided by Glenner et al., Biochem. Biophys. Res. Commun., 120:885-890 (1984) The isolation procedure and the sequence data for the first 28 amino acids are described in U.S. Pat. No. 4,666,829.

Molecular biological and protein chemical analyses have shown that the β-amyloid peptide is a small fragment of a much larger precursor protein termed the amyloid precursor protein (APP), that is normally produced by cells in many tissues of various animals, including humans. Knowledge of the structure of the gene encoding APP has demonstrated that β-amyloid peptide arises as a peptide fragment that is cleaved from APP by protease enzyme(s). Sequential processing of the precursor protein by the enzymes referred to generically as beta- and gamma-secretases, give rise to the β-amyloid peptide fragment. Both enzymes have now been molecularly cloned, and characterized to differing levels.

Several lines of evidence indicate that progressive cerebral deposition of β-amyloid peptide plays a seminal role in the pathogenesis of AD and can precede cognitive symptoms by years or decades. See, for example, Selkoe, Neuron, 6:487-498 (1991). The most important line of evidence is the discovery that missense DNA mutations at amino acid 717 of the 770-amino acid isoform of APP can be found in affected members but not unaffected members of several families with a genetically determined (familial) form of AD (Goate et al., Nature, 349:704-706 (1990); Chartier Harlan et al., Nature, 353:844-846 (1989); and Murrell et al., Science, 254:97-99 (1991.) Another such mutation, known as the Swedish variant, is comprised of a double mutation changing lysine⁵⁹⁵-methionine⁵⁹⁶ to asparagine⁵⁹⁵-leucine⁵⁹⁶ (with reference to the 695 isoform was found in a Swedish family) was reported in 1992 (Mullan et al., Nature Genet., 1:345-347 (1992). Genetic linkage analyses have demonstrated that these mutations, as well as certain other mutations in the APP gene, are the specific molecular cause of AD in the affected members of such families. In addition, a mutation at amino acid 693 of the 770-amino acid isoform of APP has been identified as the cause of the β-amyloid peptide deposition disease, HCHWA-D, and a change from alanine to glycine at amino acid 692 appears to cause a phenotype that resembles AD is some patients but HCHWA-D in others. The discovery of these and other mutations in APP in genetically based cases of AD prove that alteration of APP metabolism, and subsequent deposition of its β-amyloid peptide fragment, can cause AD.

Despite the progress which has been made in understanding the underlying mechanisms of AD and other β-amyloid peptide related diseases, there remains a need to develop methods and compositions for treatment of the disease(s). Ideally, the treatment methods would advantageously be based on drugs which are capable of inhibiting β-amyloid peptide release and/or its synthesis in vivo.

One approach toward inhibiting amyloid peptide synthesis in vivo is by inhibiting gamma secretase, the enzyme responsible for the carboxy-terminal cleavage resulting in production of β-amyloid peptide fragments of 40 or 42 residues in length. The immediate substrates for gamma secretase are β-cleaved, as well as a-cleaved carboxy-terminal fragments (CTF) of APP. The gamma-secretase cleavage site on β- and α-CTF fragments occurs in the predicted transmembrane domain of APP. Inhibitors of gamma-secretase have been demonstrated to effect amyloid pathology in transgenic mouse models (Dovey, H. F., V. John, J. P. Anderson, L. Z. Chen, P. de Saint Andrieu, L. Y. Fang, S. B. Freedman, B. Folmer, E. Goldbach, E. J. Holsztynska et al. (2001). “Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain.” J Neurochem 76(1): 173-81.)

Gamma secretase is recognized to be a multi-subunit complex comprised of the presenilins (PS1 or PS2), Nicastrin, Aph-1, and Pen 2 (De Strooper, B. (2003). “Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex.” Neuron 38(1): 9-12; Edbauer, D., E. Winkler, J. T. Regula, B. Pesold, H. Steiner and C. Haass (2003). “Reconstitution of gamma-secretase activity.” Nat Cell Biol 5(5): 486-8; Kimberly, W. T., M. J. LaVoie, B. L. Ostaszewski, W. Ye, M. S. Wolfe and D. J. Selkoe (2003). “Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2.” Proc Natl Acad Sci USA 100(11): 6382-7). Much evidence indicates that PS comprises the catalytic moiety of the complex, while the other identified subunits are necessary for proper maturation and sub-cellular localization of the active enzyme complex (reviewed in De Strooper, B. (2003). “Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex.” Neuron 38(1): 9-12.) Consistent with this hypothesis: PS knock-out mice exhibit significant reductions in β-amyloid production (De Strooper, B., P. Saftig, K. Craessaerts, H. Vanderstichele, G. Guhde, W. Annaert, K. Von Figura and F. Van Leuven (1998). “Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein.” Nature 391(6665): 387-90; Haass, C. and D. J. Selkoe (1998). “Alzheimer's disease. A technical KO of amyloid-beta peptide.” Nature 391(6665): 339-40; Herreman, A., L. Serneels, W. Annaert, D. Collen, L. Schoonjans and B. De Strooper (2000). “Total inactivation of gamma-secretase activity in presenilin-deficient embryonic stem cells.” Nat Cell Biol 2(7): 461-2); point mutations of putative active site aspartate residues in PS trans-membrane domains inhibit β-amyloid production in cells in a dominant negative fashion (Wolfe, M. S., W. Xia, B. L. Ostaszewski, T. S. Diehl, W. T. Kimberly and D. J. Selkoe (1999). “Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity.” Nature 398(6727): 513-7; Kimberly, W. T., W. Xia, T. Rahmati, M. S. Wolfe and D. J. Selkoe (2000). “The transmembrane aspartates in presenilin 1 and 2 are obligatory for gamma-secretase activity and amyloid beta-protein generation.” J Biol Chem 275(5): 3173-8); active site directed substrate-based transition state isosteres designed to inhibit gamma secretase directly conjugate to PS (Esler, W. P., W. T. Kimberly, B. L. Ostaszewski, T. S. Diehl, C. L. Moore, J. Y. Tsai, T. Rahmati, W. Xia, D. J. Selkoe and M. S. Wolfe (2000). “Transition-state analogue inhibitors of gamma-secretase bind directly to presenilin-1.” Nat Cell Biol 2(7): 428-34; Li, Y. M., M. Xu, M. T. Lai, Q. Huang, J. L. Castro, J. DiMuzio-Mower, T. Harrison, C. Lellis, A. Nadin, J. G. Neduvelil et al. (2000). “Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1.” Nature 405(6787): 689-94); finally, allosteric gamma secretase inhibitors have likewise been demonstrated to bind directly to PS (Seiffert, D., J. D. Bradley, C. M. Rominger, D. H. Rominger, F. Yang, J. E. Meredith, Jr., Q. Wang, A. H. Roach, L. A. Thompson, S. M. Spitz et al. (2000). “Presenilin-1 and -2 are molecular targets for gamma-secretase inhibitors.” J Biol Chem 275(44): 34086-91.)

Current evidence indicates that in addition to APP processing leading to β-amyloid synthesis, gamma-secretase also mediates the intra-membrane cleavage of other type I transmembrane proteins (reviewed in Fortini, M. E. (2002). “Gamma-secretase-mediated proteolysis in cell-surface-receptor signaling.” Nat Rev Mol Cell Biol 3(9): 673-84, see also Struhl, G. and A. Adachi (2000). “Requirements for presenilin-dependent cleavage of notch and other transmembrane proteins.” Mol Cell 6(3): 625-36.) Noteworthy among the known substrates of gamma-secretase is mammalian Notch 1. The Notch 1 protein is important for cell fate determination during development, and tissue homeostasis in the adult. Upon ligand engagement via the Notch ecto-domain, Notch undergoes sequential extra-cellular and intra-membrane processing analogous to APP. The intra-membrane processing of Notch mediated by gamma secretase leads to release of the Notch intracellular domain (NICD). The NICD fragment mediates Notch signaling via translocation to the nucleus, where it regulates expression of genes mediating cellular differentiation in many tissues during development, as well as in the adult.

Disruption of Notch signaling via genetic knock-out (KO) results in embryonic lethal phenotype in mice (Swiatek, P. J., C. E. Lindsell, F. F. del Amo, G. Weinmaster and T. Gridley (1994). “Notch1 is essential for postimplantation development in mice.” Genes Dev 8(6): 707-19; Conlon, R. A., A. G. Reaume and J. Rossant (1995). “Notch1 is required for the coordinate segmentation of somites.” Development 121(5): 1533-45.) The Notch KO phenotype is very similar to the phenotype observed PS1 KO mice, and precisely reproduced by PS1/PS2 double KO mice (De Strooper et al. (1998). “Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein.” Nature 391(6665): 387-90; Donoviel, D. B., A. K. Hadjantonakis, M. Ikeda, H. Zheng, P. S. Hyslop and A. Bernstein (1999). “Mice lacking both presenilin genes exhibit early embryonic patterning defects.” Genes Dev 13(21): 2801-10; Herreman, A., L. Serneels, W. Annaert, D. Collen, L. Schoonjans and B. De Strooper (2000). “Total inactivation of gamma-secretase activity in presenilin-deficient embryonic stem cells.” Nat Cell Biol 2(7): 461-2.) This convergence of phenotypes observed in knock-out mice of either the substrate (Notch) or the enzyme (PS) suggests that inhibitors of gamma secretase that also inhibit Notch function may be limited as therapeutic agents owing to the importance of Notch function in adult tissues (Fortini, M. E. (2002). “Gamma-secretase-mediated proteolysis in cell-surface-receptor signaling.” Nat Rev Mol Cell Biol 3(9): 673-84.) As APP knock-out mice develop normally and without an overt phenotype Zheng, H., M. Jiang, M. E. Trumbauer, R. Hopkins, D. J. Sirinathsinghji, K. A. Stevens, M. W. Conner, H. H. Shunt, S. S. Sisodia, H. Y. Chen et al. (1996). “Mice deficient for the amyloid precursor protein gene.” Ann NY Acad Sci 777: 421-6; Zheng, H., M. Jiang, M. E. Trumbauer, D. J. Sirinathsinghji, R. Hopkins, D. W. Smith, R. P. Heavens, G. R. Dawson, S. Boyce, M. W. Conner et al. (1995). “beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity.” Cell 81(4): 525-31, the cumulative evidence, therefore, suggests that preferred gamma secretase inhibitors would have selectivity for inhibiting gamma secretase processing of APP over gamma secretase processing of Notch.

SUMMARY OF THE INVENTION

In a broad aspect, the invention provides compounds of Formula I:

or a pharmaceutically acceptable salt thereof wherein

-   n is 1, 2, or 3; -   R₁ is aryl C₁-C₈ alkyl, aryl C₂-C₆ alkenyl, or arylalkynyl, wherein     the aryl group is optionally substituted with 1, 2, 3, 4, or 5     groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,     haloalkyl, haloalkoxy, heteroaryl, heteroaryl(C₁-C₆)alkoxy,     arylalkoxy, aryloxy, C₁-C₆ alkoxycarbonyl, —O—CH₂CH₂—O—, —O—CH₂—O—,     —C(O)NR₃₀R₃₁, —NHR′, —NR′R″, —N(R₁₆)C(O)—R₁₇, heterocycloalkyl,     phenyl, aryl C₁-C₆ alkanoyl, phenylalkoxy, phenyloxy, CN, —SO₂-aryl,     —S(O)_(x)—R₂₅, —(C₁-C₄ alkyl)-S(O)_(x)—R₂₅, —(C₁-C₄ alkyl)-SO₂-aryl,     OH, C₁-C₆ thioalkoxy, C₂-C₆ alkenyl, —O—SO₂-aryl, CO₂H,     -   wherein the heteroaryl portions of the above group are         optionally substituted with 1, 2, or 3 groups that are         independently C₁-C₆ alkyl, heteroaryl optionally substituted         with 1 or 2 groups that are independently halogen, alkyl,         alkoxy, haloalkyl, haloalkoxy, alkoxyalkyl or CN (in one aspect,         pyridyl, thienyl, furanyl, imidazolyl, or pyrazolyl), C₁-C₆         alkoxy, C₁-C₄ alkoxy C₁-C₄ alkyl, C₃-C₆ cycloalkyl, halogen, or         phenyl optionally substituted with 1, 2, 3, 4 or 5 groups that         are independently halogen, OH, C₁-C₆ alkyl, C₁-C₄ alkoxy, CF₃,         OCF₃, CN, or C₁-C₆ thioalkoxy,     -   wherein the heterocycloalkyl and aryl portions of the above         substituents are optionally substituted with 1 or 2 groups that         are independently heteroaryl optionally substituted with 1 or 2         groups that are independently halogen, alkyl, alkoxy, haloalkyl,         haloalkoxy, alkoxyalkyl or CN, (in one aspect, pyridyl, thienyl,         furanyl, imidazolyl, or pyrazolyl), C₁-C₆ alkyl, C₁-C₆ alkoxy,         C₁-C₄ alkoxy C₁-C₄ alkyl, C₃-C₆ cycloalkyl, halogen, or phenyl         optionally substituted with 1, 2, 3, 4 or 5 groups that are         independently halogen, OH, C₁-C₆ alkyl, C₁-C₄ alkoxy, CF₃, OCF₃,         CN, or C₁-C₆ thioalkoxy,     -   R₁₆ is H or C₁-C₆ alkyl;     -   R₁₇ is C₁-C₆ alkyl, aryl, heteroaryl, C₁-C₆ alkoxy, OH, aryloxy,         heteroaryloxy, aryl(C₁-C₆)alkoxy, —NR₁₈R₁₉, cycloalkyl, or         arylalkyl, wherein the cyclic portions of each of the above are         optionally substituted with 1, 2, 3, 4, or 5 groups that are         independently alkyl, alkoxy, halo, haloalkyl, haloalkoxy, CN,         NH₂, NH(alkyl), N(alkyl)(alkyl), CO₂H, or C₁-C₆ alkoxycarbonyl;         -   R₁₈ and R₃₉ are independently H, C₁-C₆ alkyl, aryl,             heteroaryl, heterocycloalkyl or aryl(C₁-C₆)alkyl, wherein             the cyclic portions of each are optionally substituted with             1, 2, or 3 groups that are independently alkyl, alkoxy,             halogen, hydroxyl, CF₃, or OCF₃;     -   wherein R′ at each occurrence is independently H, C₁-C₆ alkyl,         aryl, aryl(C₁-C₄)alkyl, C₁-C₆ alkanoyl, C₃-C₈ cycloalkyl,         aryl(C₁-C₆)alkanoyl, heterocycloalkyl, heteroaryl(C₁-C₄)alkyl,         —SO₂-alkyl, —SO₂-aryl, —SO₂-heteroaryl,         heterocycloalkyl(C₁-C₆)alkanoyl, or heteroaryl(C₁-C₆)alkanoyl,         wherein the alkyl portion of the alkyl and alkanoyl groups are         optionally substituted with halogen or C₁-C₆ alkoxy, wherein the         aryl, and heteroaryl groups are optionally substituted with         alkyl, alkoxy, halogen, haloalkyl, haloalkoxy,     -   wherein R″ at each occurrence is independently H, or C₁-C₆         alkyl, wherein the alkyl group is optionally substituted with         halogen, or -   R₁ is C₃-C₇ cycloalkyl(C₁-C₆ alkyl) wherein the cyclic portion is     optionally substituted with 1, 2, 3, 4, or 5 groups that are     independently halogen, C₁-C₆ alkyl, OH, alkoxycarbonyl, or C₁-C₆     alkoxy; or -   R₁ is C₁-C₁₄ alkyl, C₂-C₁₆ alkenyl, or C₂-C₈ alkynyl, each of which     is optionally substituted with 1 or 2 groups that are independently     OH, halogen, C₁-C₆ alkoxy, aryl, arylalkoxy, aryloxy, heteroaryl,     heterocycloalkyl, aryl(C₁-C₆)alkyl, —CO₂—(C₁-C₆ alkyl), —NR′R″,     C₁-C₆ thioalkoxy, —NH—S(O)_(x)—R₂₅, —N(C₁-C₆ alkyl)-S(O)_(x)—R₂₅,     —S(O)_(x)—R₂₅, —C(O)NR₃₀R₃₁, —N(R₁₆)C(O)NR₁₆R₁₇, or —N(R₁₆)C(O)—R₁₇;     -   wherein the above aryl groups are optionally substituted with 1,         2, or 3 groups that are independently OH, C₁-C₆ alkoxy, C₁-C₆         alkyl, or halogen;     -   R₃₀ and R₃₁ are independently H, C₁-C₆ alkyl, aryl (preferably         phenyl), arylalkyl (preferably benzyl), heteroaryl,         heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl,         arylalkanoyl, alkenyl, cycloalkyl, alkynyl, cycloalkenyl,         pyridyl, imidazolyl, thiazolyl, oxazolyl, or indolyl,         -   wherein the alkyl portions of the above are optionally             substituted with 1, 2, or 3 groups that are independently             NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆ alkyl), OH, C₁-C₆             thioalkoxy, heterocycloalkyl, aryl, heteroaryl, CN, halogen,             or alkoxy optionally substituted with OH or phenyl, wherein             the aryl, heteroaryl and heterocycloalkyl groups are             optionally substituted with 1, 2, or 3 groups that are             independently C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, OCF₃, OH,             halogen, thioalkoxy, phenyl or heteroaryl;         -   or     -   R₃₀, R₃₁, and the nitrogen to which they are attached form a         heterocycloalkyl ring containing from 3 to 7 ring members,         wherein     -   the cyclic portions of R₃₀ and R₃₁ or the heterocyclic ring         formed from R₃₀, R₃₁, and the nitrogen to which they are         attached are optionally substituted with 1, 2, or 3 groups that         are independently alkyl, alkoxy, halo, OH, thioalkoxy, NH₂,         NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆ alkyl), CF₃, OCF₃, phenyl         optionally substituted with a halogen, —(C₁-C₄ alkyl)-N(H or         C₁-C₄ alkyl)-phenyl, C₁-C₄ hydroxyalkyl, arylalkoxy, arylalkyl,         arylalkanoyl, C(O)NH₂, C(O)NH(C₁-C₆ alkyl), C(O)N(C₁-C₆         alkyl)(C₁-C₆ alkyl), heterocycloalkylalkyl, C₁-C₆         alkoxycarbonyl, C₂-C₆ alkanoyl, heteroaryl, or —SO₂—(C₁-C₆         alkyl)     -   x is 0, 1, or 2;     -   R₂₅ is C₁-C₆ alkyl, OH, NR₂₆R₂₇;         -   R₂₆ and R₂₇ are independently H, C₁-C₆ alkyl, phenyl(C₁-C₄             alkyl), aryl, or heteroaryl; or     -   R₂₆, R₂₇ and the nitrogen to which they are attached form a         heterocycloalkyl ring; -   R₁ is heteroaryl(C₁-C₆)alkyl wherein the cyclic portion is     optionally substituted with 1, 2, 3, 4, or 5 groups that are     independently halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₄ haloalkyl,     C₁-C₄ haloalkoxy, aryl, arylalkyl, aryloxy, heteroaryl, —SO₂-aryl,     —S(O)_(x)—R₂₅, —(C₁-C₄ alkyl)-S(O)_(x)—R₂₅, CN, C₁-C₆ thioalkoxy,     C₁-C₆ alkoxycarbonyl, —NR′R″, —C(O)—NR′R″, heterocycloalkyl,     -   wherein the above aryl groups are optionally substituted with 1,         2, 3, or 4 groups that are independently halogen, C₁-C₆ alkyl,         C₁-C₆ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, or CN;     -   wherein the above heteroaryl and heterocycloalkyl groups are         optionally substituted with 1, 2, or 3 groups that are         independently halogen, CF₃, (C₁-C₄)alkyl, C₁-C₆ thioalkoxy, OH,         C₁-C₄ hydroxyalkyl, or C₁-C₄ alkoxy; or -   R₁ is heterocycloalkyl(C₁-C₆ alkyl) wherein the cyclic portion is     optionally substituted with 1, 2, 3, 4, or 5 groups that are     independently halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₄ haloalkyl,     C₁-C₄ haloalkoxy, aryl, arylalkyl, aryloxy, heteroaryl, —SO₂-aryl,     —S(O)_(x)—R₂₅, —(C₁-C₄ alkyl)-S(O)_(x)—R₂₅, CN, C₁-C₆ thioalkoxy,     C₁-C₆ alkoxycarbonyl, —NR′R″, —C(O)—NR′R″, heterocycloalkyl; -   R₂ is H, C₁-C₆ alkyl, or phenyl(C₁-C₄)alkyl; -   R₃ is H, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, CN, -   R₄ is H, halogen, C₁-C₆ alkyl optionally substituted with     —CO₂—(C₁-C₆ alkyl), C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,     CN, aryloxy, isocyanato, —SO₂—(C₁-C₆ alkyl), —NHR′, —NR′R″, C₁-C₆     alkanoyl, heteroaryl, aryl, or -   R₃ and R₄ and the carbons to which they are attached form a     heterocycloalkyl ring which is optionally substituted with 1, 2, or     3 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,     or C₁-C₄ alkanoyl wherein the alkanoyl group is optionally     substituted with up to 3 halogen atoms; -   R_(3′) is H, —SO₂—NR′R″, halogen, or -   R₄ and R_(3′) and the carbons to which they are attached form a     benzo ring; or -   R₄ and R_(3′) and the carbons to which they are attached form a     1-oxa-2,3-diazacyclopentyl ring; -   R₁₀ and R₁₁ are independently H or F; or -   R₁₀, R₃, and the carbons to which they are attached for a     1,2,5-oxadiazolyl ring; or -   R₁₀, R₃, and the carbons to which they are attached form a naphthyl     ring.

The compounds of Formula I inhibit β-amyloid peptide release and/or its synthesis and, therefore, are useful in the prevention of Alzheimer's Disease (AD) in patients susceptible to AD and/or in the treatment of patients with AD in order to inhibit further deterioration in their condition. The invention also, encompasses pharmaceutical compositions containing the compounds of Formula I, and methods employing such compounds or compositions in the treatment of cognitive diseases, including Alzheimer's disease.

The invention also provides a method of treating a patient who has, or in preventing a patient from getting, a disease or condition selected from the group consisting of Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating patients with mild cognitive impairment (MCI) and preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating Down's syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, age related macular degeneration or diffuse Lewy body type of Alzheimer's disease and who is in need of such treatment which comprises administration of a therapeutically effective amount of a compound of formula (I).

In another aspect, the invention provides methods of preparing the compounds of interest, as well as intermediates useful in preparing the compounds of interest.

DETAILED DESCRIPTION OF THE INVENTION

In another aspect, the invention provides compounds of formula I-a, i.e., compounds of formula I wherein

-   R₁ is phenyl(C₁-C₉ alkyl), naphthyl(C₁-C₉ alkyl), phenyl(C₂-C₆     alkenyl), or naphthyl(C₂-C₆ alkenyl), wherein the cyclic portion of     each is optionally substituted with 1, 2, 3, 4, or 5 groups that are     independently     -   C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, CF₃, OCF₃, thiazolyl,         oxazolyl, pyrazolyl, thiazolyl(C₁-C₆)alkoxy,         pyridyl(C₁-C₆)alkoxy, phenyl(C₁-C₆ alkanoyl)phenyl(C₁-C₄)alkoxy,         oxazolyl(C₁-C₄)alkoxy, pyrazolyl(C₁-C₄)alkoxy, phenyloxy, C₁-C₆         alkoxycarbonyl, triazolyl, —O—CH₂CH₂—O—, —O—CH₂—O—,         —C(O)NR₃₀R₃₁, —NHR′, —NR′R″, —N(R₁₆)C(O)—R₁₇, morpholinyl,         thiomorpholinyl, thiomorpholinyl S,S-dioxide, piperidinyl,         pyrrolidinyl, phenyl, CN, —SO₂-phenyl, —S(O)_(x)—R₂₅, —(C₁-C₄         alkyl)-S(O)_(x)—R₂₅, —(C₁-C₄ alkyl)-SO₂-phenyl, OH, C₁-C₆         thioalkoxy, C₂-C₆ alkenyl, —O—SO₂-phenyl, or hydroxyalkyl,         -   wherein the heteroaryl group is optionally substituted with             1, 2, or 3 groups that are independently C₁-C₆ alkyl, C₁-C₆             alkoxy, or halogen,         -   wherein the heterocycloalkyl group is optionally substituted             with C₁-C₆ alkyl, C₁-C₆ alkoxy, or halogen,         -   wherein the above phenyl groups are optionally substituted             with 1, 2, 3, 4 or 5 groups that are independently halogen,             C₁-C₆ alkyl, or C₁-C₄ alkoxy,         -   R₁₆ is H or C₁-C₆ alkyl;         -   R₁₇ is C₁-C₆ alkyl, phenyl, pyridyl, pyrimidyl, pyridazyl,             pyrazinyl, thienyl, oxazolyl, thiazolyl, furanyl, C₁-C₆             alkoxy, OH, phenyloxy, pyridyloxy, pyrimidyloxy,             pyridazyloxy, pyrazinyloxy, thienyloxy, oxazolyloxy,             thiazolyloxy, furanyloxy, phenyl(C₁-C₆)alkoxy, or —NR₁₈R₁₉;         -   R₁₈ and R₁₉ are independently H, C₁-C₆ alkyl, phenyl,             pyridyl, thienyl, furanyl, piperidinyl, pyrrolidinyl,             dioxolanyl, dioxanyl, morpholinyl, thiomorpholinyl,             thiomorpholinyl 1,1-dioxide, tetrahydro-thiopyranyl             1,1-dioxide, or phenyl(C₁-C₆)alkyl; -   R₁ is C₃-C₇ cycloalkyl(C₁-C₆ alkyl) wherein the cyclic portion is     optionally substituted with 1, 2, 3, 4, or 5 groups that are     independently halogen, C₁-C₆ alkyl, OH, alkoxycarbonyl, or C₁-C₆     alkoxy; or -   R₁ is C₁-C₁₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, each of which     is optionally substituted with 1 or 2 groups that are independently     OH, halogen, C₁-C₆ alkoxy, phenyl, naphthyl, pyridyl,     phenyl(C₁-C₄)alkoxy, phenyloxy, —CO₂—(C₁-C₆ alkyl), —NR′R″, C₁-C₆     thioalkoxy, CN, —NH—S(O)_(x)—R₂₅, —N(C₁-C₆ alkyl)-S(O)_(x)—R₂₅,     —S(O)_(x)—R₂₅, —C(O)NR₃₀R₃₁, —N(R₁₆)C(O)NR₁₆R₁₇, or —N(R₁₆)C(O)—R₁₇;     -   wherein the above cyclic portions of the above groups are         optionally substituted with 1, 2, 3, or 4 groups that are         independently OH, C₁-C₆ alkoxy, C₁-C₆ alkyl, or halogen;     -   R₂₅ is C₁-C₆ alkyl, OH, NR₂₆R₂₇;         -   R₂₆ and R₂₇ are independently H, C₁-C₆ alkyl, phenyl(C₁-C₄             alkyl), phenyl, naphthyl, or pyridyl, pyrimidyl, pyridazyl,             pyrazinyl, thienyl, oxazolyl, thiazolyl, furanyl; or         -   R₂₆, R₂₇ and the nitrogen to which they are attached form a             5, 6, or 7 membered heterocycloalkyl ring;     -   or -   R₁ is thienyl(C₁-C₆ alkyl), pyridyl(C₁-C₆ alkyl), furanyl(C₁-C₆     alkyl), pyrazolyl(C₁-C₆ alkyl), pyrrolyl(C₁-C₆ alkyl),     thiazolyl(C₁-C₆ alkyl), 1,2,3-thiadiazolyl(C₁-C₆ alkyl),     1,2,4-thiadiazolyl(C₁-C₆ alkyl), 1,3,4-oxadiazole(C₁-C₆ alkyl),     1,2,4-oxadiazole(C₁-C₆ alkyl), indolyl(C₁-C₆ alkyl), triazolyl(C₁-C₆     alkyl), imidazolyl(C₁-C₆ alkyl), isoxazolyl(C₁-C₆ alkyl),     benzothienyl(C₁-C₆ alkyl), benzofuranyl(C₁-C₆ alkyl),     quinolinyl(C₁-C₆ alkyl), imidazo[2,1-b]thiazolyl(C₁-C₆ alkyl),     benzo[c][1,2,5]thiadiazolyl(C₁-C₆ alkyl), benzoimidazolyl(C₁-C₆     alkyl), benzooxazolyl(C₁-C₆ alkyl), benzo[1,2,5]oxadiazolyl(C₁-C₆     alkyl), 1H-indazolyl(C₁-C₆ alkyl), 1H-benzotriazolyl(C₁-C₆ alkyl),     furo[3,2-b]pyridinyl(C₁-C₆ alkyl), 1H-pyrazolo[3,4-b]pyridinyl(C₁-C₆     alkyl), 1H-pyrazolo[3,4-c]pyridinyl(C₁-C₆ alkyl), quinoxalinyl(C₁-C₆     alkyl), or isoquinolinyl(C₁-C₆ alkyl),     -   wherein the cyclic portions of each of the above are optionally         substituted with 1, 2, 3, 4, or 5 groups that are independently         halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₄ haloalkyl, C₁-C₄         haloalkoxy, phenyl, phenyl(C₁-C₆ alkyl), phenyloxy, pyrazolyl,         imidazolyl, furanyl, thienyl, morpholinyl, —SO₂-phenyl,         —SO₂—(C₁-C₆ alkyl), —S(O)_(x)—R₂₅, —(C₁-C₄ alkyl)-S(O)_(x)—R₂₅,         CN, C₁-C₆ thioalkoxy, C₆-C₆ alkoxycarbonyl, —NR′R″, —C(O)—NR′R″,         pyridyl, piperidinyl, piperazinyl, pyrrolidinyl, or         tetrahydrofuranyl,         -   wherein the above phenyl groups are optionally substituted             with 1, 2, 3, or 4 groups that are independently halogen,             C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₄ haloalkyl, C₁-C₄             haloalkoxy, or CN;         -   wherein the above heteroaryl and heterocycloalkyl groups are             optionally substituted with 1, 2, or 3 groups that are             independently halogen, CF₃, (C₁-C₄)alkyl, C₁-C₆ thioalkoxy,             or C₁-C₄ alkoxy;     -   R′ is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl,         phenyl(C₁-C₄)alkyl, C₁-C₆ alkanoyl, phenyl(C₁-C₆)alkanoyl,         pyridyl(C₁-C₄)alkyl, pyrimidyl(C₁-C₄)alkyl,         pyridazyl(C₁-C₄)alkyl, pyrazinyl(C₁-C₄)alkyl,         thienyl(C₁-C₄)alkyl, oxazolyl(C₁-C₄)alkyl,         thiazolyl(C₁-C₄)alkyl, furanyl(C₁-C₄)alkyl,         piperidinyl(C₁-C₄)alkyl, —SO₂-alkyl, —SO₂-phenyl, —SO₂-pyridyl,         —SO₂-pyrimidyl, —SO₂-pyridazyl, —SO₂-pyrazinyl, —SO₂-thienyl,         —SO₂-oxazolyl, —SO₂-thiazolyl, —SO₂-furanyl,         pyridyl(C₁-C₆)alkanoyl, pyrimidyl(C₁-C₆)alkanoyl,         pyridazyl(C₁-C₆)alkanoyl, pyrazinyl(C₁-C₆)alkanoyl,         thienyl(C₁-C₆)alkanoyl, oxazolyl(C₁-C₆)alkanoyl,         thiazolyl(C₁-C₆)alkanoyl, or furanyl(C₁-C₆)alkanoyl, wherein the         alkyl portion of the alkyl and alkanoyl groups are optionally         substituted with halogen or C₁-C₆ alkoxy,         -   wherein the aryl, and heteroaryl groups are optionally             substituted with alkyl, alkoxy, halogen, haloalkyl,             haloalkoxy,     -   R″ is H, or C₁-C₆ alkyl, wherein the alkyl group is optionally         substituted with halogen, or     -   R₁ is 4-oxo-4H-chromenyl(C₁-C₆ alkyl), 2H-chromenyl(C₁-C₆         alkyl), pyrrolidinonyl dione(C₁-C₆ alkyl), pyrrolidinonyl(C₁-C₆         alkyl), isoindolyl dione(C₁-C₆ alkyl), 1,3-dioxolanyl(C₁-C₆         alkyl), dioxanyl(C₁-C₆ alkyl), tetrahydropyranyl(C₁-C₆ alkyl),         indolinyl(C₁-C₆ alkyl),         3-oxo-1,3-dihydro-benzo[c]isoxazolyl(C₁-C₆ alkyl),         2-oxo-2,3-dihydro-1H-benzoimidazolyl(C₁-C₆ alkyl),         3-oxo-3,4-dihydro-1H-2-oxa-3lambda4-thia-1,4-diaza-naphthyl(C₁-C₆         alkyl), 3,3-dimethyl-3H-indazolyl(C₁-C₆ alkyl), or         piperidinyl(C₁-C₆ alkyl), wherein the cyclic portion of each is         optionally substituted with 1, 2, 3, 4, or 5 groups that are         independently halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₄         haloalkyl, C₁-C₄ haloalkoxy, phenyl, phenyl(C₁-C₆ alkyl),         phenyloxy, pyrazolyl, imidazolyl, furanyl, thienyl, morpholinyl,         —SO₂-phenyl, —SO₂—(C₁-C₆ alkyl), —S(O)_(x)—R₂₅, —(C₁-C₄         alkyl)-S(O)_(x)—R₂₅, CN, C₁-C₆ thioalkoxy, C₁-C₆ alkoxycarbonyl,         —NR′R″, —C(O)—NR′R″, pyridyl, piperidinyl, piperazinyl,         pyrrolidinyl, or tetrahydrofuranyl,         -   wherein the above phenyl groups are optionally substituted             with 1, 2, 3, or 4 groups that are independently halogen,             C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₄ haloalkyl, C₁-C₄             haloalkoxy, or CN;         -   wherein the above heteroaryl and heterocycloalkyl groups are             optionally substituted with 1, 2, or 3 groups that are             independently halogen, CF₃, (C₁-C₄)alkyl, C₁-C₆ thioalkoxy,             or C₁-C₄ alkoxy; -   R₂ is H, C₁-C₄ alkyl, or benzyl; -   R₃ is H, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, CF₃, CN, -   R₄ is H, halogen, C₁-C₆ alkyl optionally substituted with     —CO₂—(C₁-C₆ alkyl), C₁-C₆ alkoxy, C₁-C₆ haloalkyl, OCF₃, CN,     phenyloxy, isocyanato, —SO₂—(C₁-C₆ alkyl), —NHR′, —NR′R″, C₁-C₆     alkanoyl, oxazolyl, pyrazolyl, thiazolyl, pyridyl, furanyl or     thienyl, phenyl, or -   R₃ and R₄ and the carbons to which they are attached form a     piperidinyl or pyrrolidinyl ring which is optionally substituted     with 1, 2, or 3 groups that are independently C₁-C₄ alkyl, C₁-C₄     alkoxy, halogen, or C₁-C₄ alkanoyl wherein the alkanoyl group is     optionally substituted with up to 3 halogen atoms; -   R_(3′) is H, —SO₂—NR′R″, or halogen; -   or -   R₄ and R_(3′) and the carbons to which they are attached form a     benzo ring.

Preferred compounds of formula I include those of formula

wherein

-   alk is

wherein

-   -   m is 0, 1, 2, 3, 4, 5, or 6;     -   R₂₀ is H or methyl; and the alk group is optionally substituted         with phenyl;

-   R₅ is H, C₁-C₆ alkoxy, CF₃, morpholinyl, oxazolyl, pyrazolyl,     thiomorpholinyl, thiomorpholinyl S,S-dioxide, piperidinyl,     pyrrolidinyl, halogen, C₁-C₆ alkyl, phenyl optionally substituted     with 1, 2, 3, 4 or 5 groups that are independently halogen, C₁-C₆     alkyl, or C₁-C₄ alkoxy, morpholin-4-yl, phenyl,     —O—(CH₂)—C(O)O—(CH₂CH₃), CN, —(C₁-C₄ alkyl)-SO₂-phenyl,

-   R₆ is H, C₁-C₆ alkoxy, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, CF₃,     OCF₃, phenyl(C₁-C₄)alkoxy, phenyloxy, C₁-C₆ alkoxycarbonyl, CN,     C₂-C₆ alkenyl, wherein the above phenyl groups are optionally     substituted with 1, 2, 3, 4 or 5 groups that are independently     halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₄ alkoxy, C₁-C₄     alkoxycarbonyl, or benzyloxy; or

-   R₅, R₆, and the carbons to which they are attached form a benzo     ring, which is optionally substituted with 1 or 2 groups that are     independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃;

-   R₇ is H, OH, C₁-C₆ alkoxy, CO₂H, haloalkyl, CN, triazolyl,     tetrazolyl, NO₂, phenyl(C₁-C₆ alkanoyl),

-    —O—SO₂-phenyl, —S(O)_(x)—R₂₅, —(C₁-C₄ alkyl)-S(O)_(x)—R₂₅, halogen,     C₁-C₆ alkyl, phenyloxy, CF₃, C₁-C₆ alkoxycarbonyl, —(C₁-C₄     alkyl)-C(O)NR₃₉R₃₁, —O—(C₁-C₄ alkyl)-C(O)NR₃₀R₃₁, —NHR′, —NR′R″,     pyridyl, oxazolyl, oxadiazolyl, —N(R₁₆)C(O)—R₁₇,     thiazolyl(C₁-C₆)alkoxy, pyridyl(C₁-C₆)alkoxy, oxazolyl(C₁-C₄)alkoxy,     or pyrazolyl(C₁-C₄)alkoxy, wherein the cyclic portions of the above     are optionally substituted with 1, 2, or 3 groups that are     independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₄ alkoxy C₁-C₄ alkyl,     pyridyl, pyrrolyl, imidazolyl, furanyl, thienyl optionally     substituted with 1 or 2 methyls, halogen, C₃-C₆ cycloalkyl (in one     aspect, cyclohexyl) or phenyl optionally substituted with 1, 2, 3, 4     or 5 groups that are independently halogen, OH, C₁-C₆ alkyl, C₁-C₄     alkoxy, CF₃, OCF₃, CN, or C₁-C₆ thioalkoxy, or -   R₇ is methoxycarbonyl, methoxy, ethoxy, isopropoxy, ethoxy     substituted with thiazol-5-yl, wherein the thiazolyl ring is     substituted with methyl, —SCH₃, methyl, isopropyl, tert-butyl,     isobutyl, F, Br, Cl, CF₃, OCF₃, cyano, N(CH₃)₂, N(C₂ alkyl     substituted with Cl) (C₂ alkyl substituted with Cl), phenyl, phenyl     substituted with methyl, benzyloxy, NO₂, —S(O)-C₁-C₆ alkyl,     —SO₂—C₁-C₆ alkyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆ alkyl),     —N(R₁₆)C(O)R₁₇, —C(O)NR₃₀R₃₁, C₁-C₂ haloalkyl, phenyloxy,     —O—SO₂-(4-chlorophenyl), —NH—C(O)—CH₃, —O—C(O)—CH₃, thiazolyl     substituted with tert-butyl, or OH; wherein     -   R₃₀ and R₃₁ are independently H, C₁-C₆ alkyl, phenyl, phenyl         C₁-C₆ alkyl, benzyl, phenylalkanoyl, C₂-C₆ alkenyl, C₃-C₆         cycloalkyl, alkynyl, cycloalkenyl, piperidinyl optionally         substituted with C₁-C₄ alkyl or C₂-C₆ alkanoyl, pyridyl C₁-C₆         alkyl, pyrazolyl C₁-C₆ alkyl, C₂-C₆ alkynyl, tetrahydronaphthyl,         tetrahydrofuranyl, dihydrofuranonyl, cyclohexenyl, pyrrolidinyl,         pyrazolyl, naphthyl, quinuclidinyl, 4H-pyranonyl (preferably         3-hydroxy 4H-pyranonyl), 1,4-dioxanyl, tetrahydronaphthyl C₁-C₆         alkyl, tetrahydrofuranyl C₁-C₆ alkyl, cyclohexenyl C₁-C₆ alkyl,         pyrrolidinyl C₁-C₆ alkyl, pyrazolyl C₁-C₆ alkyl, naphthyl C₁-C₆         alkyl, quinuclidinyl C₁-C₆ alkyl, 4H-pyranonyl C₁-C₆ alkyl         (preferably 3-hydroxy 4H-pyranonyl C₁-C₆ alkyl), pyrazinyl C₁-C₆         alkyl, pyrrolidinyl C₁-C₆ alkyl, furanyl C₁-C₆ alkyl, thienyl         C₁-C₆ alkyl, pyrrolyl C₁-C₆ alkyl, 2,5-dihydro-1H-pyrrolyl C₁-C₆         alkyl, thiazolyl C₁-C₆ alkyl, biphenyl C₁-C₆ alkyl, benzothienyl         C₁-C₆ alkyl, furanyl C₁-C₆ alkyl, isoxazolyl C₁-C₆ alkyl,         1,4-dioxanyl C₁-C₆ alkyl, pyridyl, imidazolyl, thiazolyl,         oxazolyl, or indolyl,         -   wherein the alkyl portions of the above are optionally             substituted with 1, 2, or 3 groups that are independently             NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆ alkyl), OH,             phenyl, C₁-C₆ thioalkoxy, CN, halogen, or alkoxy optionally             substituted with OH or phenyl; or     -   R₃₀, R₃₁, and the nitrogen to which they are attached form a         heterocycloalkyl ring that is pyrrolidinyl, piperidinyl,         morpholinyl, dihydro 1H-indolyl, tetrahydroisoquinolinyl,         thiomorpholinyl, thiomorpholinyl, S,S-dioxide,         tetrahydroquinolinyl, or piperazinyl, wherein     -   the cyclic portions of R₃₀ and R₃₁ or the heterocyclic ring         formed from R₃₀, R₃₁, and the nitrogen to which they are         attached are optionally substituted with 1, 2, or 3 groups that         are independently alkyl, alkoxy, halo, thioalkoxy, OH, NH₂,         NH(C₁-C₆ alkyl), N(C₂-C₆ alkyl)(C₁-C₆ alkyl), CF₃, OCF₃, phenyl,         4-halophenyl, —(C₁-C₄ alkyl)-N(H or C₁-C₄ alkyl)-phenyl, C₁-C₄         hydroxyalkyl, phenylalkoxy, phenylalkyl, phenylalkanoyl, —(C₁-C₄         alkyl)-pyrrolidinyl, C(O)NH₂, C(O)NH(C₁-C₆ alkyl), C(O)N(C₁-C₆         alkyl)(C₁-C₆ alkyl), C₁-C₆ alkoxycarbonyl, C₂-C₆ alkanoyl,         pyrazolyl, pyrrolyl, pyridyl, furanyl, morpholinyl, or         —SO₂—(C₁-C₆ alkyl);     -   R′ is H, C₁-C₆ alkyl, or C₁-C₆ alkanoyl, wherein the alkyl         portion of the alkyl and alkanoyl groups are optionally         substituted with halogen,     -   R″ is H or C₁-C₆ alkyl, wherein the alkyl group is optionally         substituted with halogen;     -   R₁₆ is H or C₁-C₆ alkyl;     -   R₁₇ is C₁-C₆ alkyl, phenyl, pyridyl, pyrimidyl, pyridazyl,         pyrazinyl, thienyl, C₁-C₆ alkoxy, OH, phenyloxy, pyridyloxy,         pyrimidyloxy, pyridazyloxy, pyrazinyloxy, thienyloxy,         phenyl(C₁-C₄)alkoxy, phenyl C₁-C₆ alkyl, thienyl C₁-C₆ alkyl,         C₃-C₆ cycloalkyl, or phenyl C₁-C₆ alkyl, or —NR₁₈R₁₉, wherein         the cyclic portions of each of the above are optionally         substituted with 1, 2, 3, 4, or 5 groups that are independently         alkyl, alkoxy, halo, CF₃, OCF₃, CN, NH₂, NH(alkyl),         N(alkyl)(alkyl), CO₂H, or C₁-C₆ alkoxycarbonyl;     -   R₁₈and R₁₉ are independently H, C₁-C₆ alkyl, phenyl, pyridyl,         thienyl, piperidinyl, pyrrolidinyl, morpholinyl,         thiomorpholinyl, thiomorpholinyl 1,1-dioxide,         tetrahydro-thiopyranyl 1,1-dioxide, isoxazolyl or         phenyl(C₁-C₄)alkyl, wherein the cyclic portions of each are         optionally substituted with 1, 2, or 3 groups that are         independently alkyl, alkoxy, halogen, hydroxyl, CF₃, or OCF₃; or -   R₆, R₇, and the carbons to which they are attached form a benzo     ring, which is optionally substituted with 1 or 2 groups that are     independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃; -   R₈ is H, halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, or -   R₇ and R₈ are —O—CH₂CH₂—O—, or —O—CH₂—O—;     -   R₉ is H, halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, or CN.

In another aspect, the invention provides compounds of formula II-a, i.e., compounds of formula II wherein R₂, R₁₀ and R₁₁ are simultaneously H.

In another aspect, the invention provides compounds of formula II-b, i.e., compounds of formula II-a wherein

-   R₃ is H, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or CN, R₄ is     halogen, C₁-C₄ alkoxy, C₁-C₄ alkyl, CF₃, OCF₃, CN, —NHR′, —NR′R″, or     C₁-C₄ alkanoyl, -   R_(3′) is H, —SO₂—NR′R″, or halogen; or -   R₄ and R_(3′) and the carbons to which they are attached form a     benzo ring.

In another aspect, the invention provides compounds of formula II-c, i.e., compounds of formula II-b wherein

-   R₆ is H, C₁-C₆ alkoxy, halogen, CF₃, OCF₃, benzyloxy, phenyloxy,     C₁-C₄ alkoxycarbonyl, C₁-C₄ alkyl, CN, C₂-C₆ alkenyl, wherein the     above phenyl groups are optionally substituted with 1, 2, 3, 4 or 5     groups that are independently halogen, C₁-C₆ alkyl, or C₁-C₄ alkoxy, -   R₇ is H, OH, C₁-C₄ alkoxy, halogen, C₁-C₄ alkyl, CF₃, C₁-C₄     alkoxycarbonyl, —C(O)NR₃₀R₃₁, —NHR′, —NR′R″, —N(R₁₆)C(O)—R₁₇, phenyl     optionally substituted with 1, 2, 3, 4 or 5 groups that are     independently halogen, C₁-C₆ alkyl, or C₁-C₄ alkoxy, OCF₃, CN, C₁-C₄     thioalkoxy,     -   R₁₆ is H or C₁-C₆ alkyl;     -   R₁₇ is C₁-C₆ alkyl, phenyl, pyridyl, pyrimidyl, thienyl, C₁-C₆         alkoxy, OH, phenyloxy, pyridyloxy, pyrimidyloxy, thienyloxy,         phenyl(C₁-C₄)alkoxy, or —NR₁₈R₁₉;     -   R₁₈ and R₁₉ are independently H, C₁-C₆ alkyl, phenyl, pyridyl,         thienyl, piperidinyl, pyrrolidinyl, morpholinyl,         thiomorpholinyl, thiomorpholinyl 1,1-dioxide,         tetrahydro-thiopyranyl 1,1-dioxide, or phenyl(C₁-C₄)alkyl;     -   R₃₀ and R₃₁ are independently H, C₁-C₆ alkyl, phenyl, benzyl,         pyridyl, thiazolyl, oxazolyl, or indolyl, or     -   R₃₀, R₃₁, and the nitrogen to which they are attached form a         azepanyl, piperidinyl, pyrrolidinyl, morpholinyl,         thiomorpholinyl, or thiomorpholinyl 1,1-dioxide, or -   R₆, R₇, and the carbons to which they are attached form a benzo     ring, which is optionally substituted with 1 or 2 groups that are     independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃; -   R₉ is H, halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, or -   R₇ and R₉ are —O—CH₂CH₂—O—, or —O—CH₂—O—; and -   R₉ is H, halogen, C₁-C₂ alkoxy, C₁-C₂ alkyl.

In another aspect, the invention provides compounds of formula II-d, i.e., compounds of formula II-b wherein

-   R₇ is thiazolyl(C₁-C₆)alkoxy, phenyloxy, —O—SO₂-phenyl,     pyridyl(C₁-C₆)alkoxy, oxazolyl(C₁-C₄)alkoxy, pyrazolyl(C₁-C₄)alkoxy,     wherein     -   the thiazolyl, pyridyl, oxazolyl, and pyrazolyl groups are         optionally substituted with 1, 2, or 3 groups that are         independently C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ thioalkoxy, or         halogen;     -   the phenyl groups are optionally substituted with 1, 2, 3, 4 or         5 groups that are independently halogen, C₁-C₆ alkyl, or C₁-C₄         alkoxy, OCF₃, CN, C₁-C₄ thioalkoxy, or -   R₃ is H, halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl; -   R₇ and R₈ are —O—CH₂CH₂—O—, or —O—CH₂—O—; -   R₉ is H, halogen, C₁-C₂ alkoxy, C₁-C₂ alkyl.

In another aspect, the invention provides compounds of formula II-e, i.e., compounds of formula II-c wherein

-   R₄ is halogen, C₁-C₄ alkoxy (in one aspect, methoxy or ethoxy),     C₁-C₄ alkyl (in one aspect, methyl), CF₃, OCF₃, CN, —NHR′, or C₁-C₄     thioalkoxy (in one aspect, thiomethoxy or thioethoxy); and -   R₆, R₇, and the carbons to which they are attached form a benzo     ring, which is optionally substituted with 1 or 2 groups that are     independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃. In     another aspect, the phenyl ring is unsubstituted.

In another aspect, the invention provides compounds of formula II-f, i.e., compounds of formula II-c wherein R₆ and R₉ are independently H, C₁-C₄ alkyl, halogen, C₂-C₆ alkenyl C₁-C₄ alkoxy, or phenyloxy wherein the phenyl is optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, C₁-C₄ alkyl, or C₁-C₄ alkoxy; and

-   R₇ is H, OH, C₁-C₄ alkoxy, halogen, C₁-C₄ alkyl, CF₃, C₁-C₄     alkoxycarbonyl, —C(O)NR₃₀R₃₁, —NHR′, —NR′R″, —N(R₁₆)C(O)—R₁₇, OCF₃,     CN, C₁-C₄ thioalkoxy.

In another aspect, the invention provides compounds of formula II-g, i.e., compounds of formula II-f wherein

-   R₄ and R_(3′) and the carbons to which they are attached form a     benzo ring.

In another aspect, the invention provides compounds of formula II-h, i.e., compounds of formulas II-f, or II-g wherein

-   R₅, R₆, R₈, and R₉ are H.

In another aspect, the invention provides compounds of formula II-i, i.e., compounds of formulas II-c, II-f, or II-g wherein

-   R₅ is H, F or Cl; and -   R₆ is H, CN, methyl, C₂-C₄ alkenyl, or phenyloxy wherein the phenyl     is optionally substituted with 1, 2, 3, 4 or 5 groups that are     independently halogen, C₁-C₄ alkyl, or C₁-C₄ alkoxy.

In another aspect, the invention provides compounds of formula II-j, i.e., compounds of formulas II-c, II-f, II-g, II-h, or II-i wherein

-   alk is —CH₂—, or —CH(CH₃)—.

In another aspect, the invention provides compounds of formula II-k, i.e., compounds of formulas II-f, II-g, II-h, or II-i wherein R₇ is —C(O)NR₃₀R₃₁.

In another aspect, the invention provides compounds of formula II-l, i.e., compounds of formula II-c wherein

-   n is 3; -   R₃ is H, halogen, C₁-C₃ alkyl, C₁-C₃ alkoxy, CF₃, or CN, -   R₄ is halogen, C₁-C₄ alkoxy, CF₃, OCF₃, CN, —NHR′, —NR′R″, or C₁-C₄     alkanoyl, -   R_(3′) is H, or halogen; or -   R₄ and R_(3′) and the carbons to which they are attached form a     benzo ring; and -   R₇ and R₈ are —O—CH₂CH₂—O—, or —O—CH₂—O—.

In another aspect, the invention provides compounds of formula II-m, i.e., compounds of formula II-l wherein R₄ is F, Cl, Br, I or methyl. In another aspect, R₄ is Cl or Br. In still another aspect, at least one of R₃ and R_(3′) is H. In yet another aspect, R₄ if F or Cl. Still more preferably, R₄ is F or Cl and R₃, R₃₀, and R₁₁ are all H.

In another aspect, the invention provides compounds of formula II-n, i.e., compounds of formula II-l wherein

-   R₄ and R_(3′) and the carbons to which they are attached form a     benzo ring.

In another aspect, the invention provides compounds of formula II-o, i.e., compounds of formulas II-l, II-m, or II-n wherein R₃ is H, F, Cl, C₁-C₂ alkyl, C₁-C₂ alkoxy, CF₃, or CN.

In another aspect, the invention provides compounds of formula II-p, i.e., compounds of formulas II-l, II-m, II-n, or II-o wherein alk is —CH₂—, or —CH(CH₃)—.

In another aspect, the invention provides compounds of formula II-q, i.e., compounds of formula II wherein

-   R₅ is H; -   R₆, R₇ together are —O—CH₂—O—, or —O—CH₂CH₂—O—; or -   R₆ and R₇ together form a phenyl group which is optionally     substituted with methoxy; -   R₈ is H; and -   R₉ is H.

In another aspect, the invention provides compounds of formula II-r, i.e., compounds of formula II-q wherein R₄ is methyl, F, Cl or CF₃. In another aspect, R₃ is H. In still another aspect, R_(3′) is also H. In yet still another aspect, R₂, R₁₀, and R₁₁ are H. In yet another aspect, R₄ is F or Cl. In still another aspect, R₄ is Cl.

In another aspect, the invention provides compounds of formula II-s, i.e., compounds of formula II-q wherein R₄ is H. In another aspect, at least one of R₃ and R_(3′) is not H. In another aspect, neither of R₃ nor R_(3′) is H.

In still yet another aspect, the invention provides compounds of formula II-t, i.e., compounds of formula II-c, wherein R5, R6, R7, R8, and R9 are all independently halogen. In another aspect, the halogens are the same. In still another aspect, the halogen is F.

Other preferred compounds of formulas I or I-a are those of formula III

-   alk is

wherein

-   m is 0, 1, 2, 3, 4, 5, or 6; -   R₂₀ is H or methyl; -   heteroaryl is thienyl, pyridyl, furanyl, pyrazolyl, pyrrolyl,     thiazolyl, 1,2,3-thiadiazolyl, indolyl, triazolyl, benzothienyl,     benzofuranyl, quinolinyl, or imidazo[2,1-b]thiazolyl, each of which     is optionally substituted with 1, 2, 3, 4, or 5 groups that are     independently halogen, C₁-C₆ alkyl, phenyl, phenyl(C₁-C₆ alkyl),     phenyloxy, pyrazolyl, imidazolyl, furanyl, thienyl, —SO₂-phenyl, CN,     C₁-C₆ thioalkoxy, C₁-C₆ alkoxycarbonyl, —NR′R″, piperidinyl,     piperazinyl, pyrrolidinyl, or tetrahydrofuranyl,     -   wherein the above phenyl groups are optionally substituted with         1, 2, 3, or 4 groups that are independently halogen, C₁-C₆         alkyl, C₁-C₆ alkoxy, or CN;     -   wherein the pyrazolyl, imidazolyl, furanyl, and thienyl groups         are optionally substituted with 1, 2, or 3 groups that are         independently halogen, CF₃, or (C₁-C₄)alkyl;     -   wherein R′ is H, C₁-C₆ alkyl, or C₁-C₆ alkanoyl, wherein the         alkyl portion of the alkyl and alkanoyl groups are optionally         substituted with halogen,     -   wherein R″ is H, or C₁-C₆ alkyl, wherein the alkyl group is         optionally substituted with halogen.

In another aspect, the invention provides compounds of formula III-a, i.e., compounds of formula III wherein

-   R₂ is H, methyl, or benzyl; and -   R₁₀ and R₁₁ are simultaneously H.

In another aspect, the invention provides compounds of formula III-b, i.e., compounds of formula III-a wherein

-   R₃ is H, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or CN, -   R₄ is halogen, C₁-C₄ alkoxy, C₁-C₄ alkyl, CF₃, OCF₃, CN, —NHR′,     —NR′R″, or C₁-C₄ alkanoyl, and -   R_(3′) is H, —SO₂—NR′R″, or halogen; or -   R₄ and R_(3′) and the carbons to which they are attached form a     benzo ring.

In another aspect, the invention provides compounds of formula III-c, i.e., compounds of formula III-b wherein R₄ is halogen, methoxy, methyl, CF₃, OCF₃, or CN; and R_(3′) is H, or halogen.

In another aspect, the invention provides compounds of formula III-d, i.e., compounds of formula III-c wherein

-   m is 0, 1, 2, 3, or 4; -   heteroaryl is thienyl, pyridyl, furanyl, pyrazolyl, pyrrolyl,     thiazolyl, 1,2,3-thiadiazolyl, or triazolyl, each of which is     optionally substituted with 1, 2, or 3 groups that are independently     halogen, C₁-C₆ alkyl, phenyl, phenyl(C₁-C₄ alkyl), phenyloxy,     pyrazolyl, imidazolyl, furanyl, thienyl, —SO₂-phenyl, CN, C₁-C₄     thioalkoxy, C₁-C₄ alkoxycarbonyl, —NR′R″, piperidinyl, wherein     -   the above phenyl groups are optionally substituted with 1, 2, 3,         or 4 groups that are independently halogen, C₁-C₆ alkyl, C₁-C₆         alkoxy, or CN;     -   the pyrazolyl, imidazolyl, furanyl, and thienyl groups are         optionally substituted with 1, 2, or 3 groups that are         independently halogen, CF₃, or (C₁-C₄)alkyl.

In another aspect, the invention provides compounds of formula III-e, i.e., compounds of formula III-d wherein

-   m is 0, 1, or 2; -   heteroaryl is thienyl, pyridyl, furanyl, pyrazolyl, pyrrolyl,     thiazolyl, 1,2,3-thiadiazolyl, or triazolyl, wherein each is     optionally substituted with 1, 2, or 3 groups that are independently     halogen, C₁-C₆ alkyl, phenyl, benzyl, phenyloxy, pyrazolyl,     —SO₂-phenyl, CN, C₁-C₄ thioalkoxy, C₁-C₄ alkoxycarbonyl, —NR′R″,     piperidinyl, wherein     -   the above phenyl groups are optionally substituted with 1, 2, 3,         or 4 groups that are independently halogen, C₁-C₆ alkyl, C₁-C₆         alkoxy, or CN;     -   the pyrazolyl, is optionally substituted with 1, or 2, or 3         groups that are independently halogen, CF₃, or (C₁-C₄)alkyl.

In another aspect, the invention provides compounds of formula III-f, i.e., compounds of formula III-e wherein

-   m is 0; -   heteroaryl is thienyl, pyridyl, furanyl, pyrazolyl, pyrrolyl,     thiazolyl, or triazolyl, wherein each is optionally substituted with     1, 2, or 3 groups that are independently halogen, C₁-C₆ alkyl,     phenyl, benzyl, phenyloxy, pyrazolyl, —SO₂-phenyl, CN, C₁-C₄     thioalkoxy, C₁-C₄ alkoxycarbonyl, —NR′R″, piperidinyl, wherein     -   the above phenyl groups are optionally substituted with 1, 2, 3,         or 4 groups that are independently halogen, C₁-C₆ alkyl, C₁-C₆         alkoxy, or CN;     -   the pyrazolyl, is optionally substituted with 1, or 2, or 3         groups that are independently halogen, CF₃, or (C₁-C₄)alkyl.

In another aspect, the invention provides compounds of formula III-f1, i.e., compounds of formula III-e wherein

-   m is 2; -   heteroaryl is thienyl, pyridyl, furanyl, pyrazolyl, pyrrolyl,     thiazolyl, or triazolyl, wherein each is optionally substituted with     1, 2, or 3 groups that are independently halogen, C₁-C₆ alkyl,     phenyl, benzyl, phenyloxy, pyrazolyl, —SO₂—phenyl, CN, C₁-C₄     thioalkoxy, C₁-C₄ alkoxycarbonyl, —NR′R″, piperidinyl, wherein     -   the above phenyl groups are optionally substituted with 1, 2, 3,         or 4 groups that are independently halogen, C₁-C₆ alkyl, C₁-C₆         alkoxy, or CN;     -   the pyrazolyl, is optionally substituted with 1, or 2, or 3         groups that are independently halogen, CF₃, or (C₁-C₄)alkyl.

In another aspect, the invention provides compounds of formula III-g, i.e., compounds according to anyone of formulas III, III-a, III-b, III-f, or III-f1 wherein n is 1. In another aspect, n is 2. In still another aspect, n is 3.

In another aspect, the invention provides compounds of formula III-h, i.e., compounds according to formula III-b wherein

-   m is 0, 1, 2, or 3; -   heteroaryl is indolyl, benzothienyl, benzofuranyl, quinolinyl, or     imidazo[2,1-b]thiazolyl, wherein each is optionally substituted with     1, 2, or 3 groups that are independently halogen, C₁-C₆ alkyl,     phenyl, benzyl, phenyloxy, pyrazolyl, —SO₂-phenyl, CN, C₁-C₄     thioalkoxy, C₁-C₄ alkoxycarbonyl, —NR′R″, piperidinyl, wherein     -   the above phenyl groups are optionally substituted with 1, 2, 3,         or 4 groups that are independently halogen, C₁-C₆ alkyl, C₁-C₆         alkoxy, or CN;     -   the pyrazolyl, is optionally substituted with 1, or 2, or 3         groups that are independently halogen, CF₂, or (C₁-C₄)alkyl.

In another aspect, the invention provides compounds of formula III-i, i.e., compounds according to formula III-h wherein

-   m is 0 or 1; -   heteroaryl is indolyl, benzothienyl, benzofuranyl, quinolinyl, or     imidazo[2,1-b]thiazolyl, wherein each is optionally substituted with     1, 2, or 3 groups that are independently halogen, C₁-C₆ alkyl,     phenyl, benzyl, phenyloxy, pyrazolyl, —SO₂-phenyl, CN, C₁-C₄     thioalkoxy, C₁-C₄ alkoxycarbonyl, —NR′R″, piperidinyl, wherein     -   the above phenyl groups are optionally substituted with 1, 2, 3,         or 4 groups that are independently halogen, C₁-C₆ alkyl, C₁-C₆         alkoxy, or CN;     -   the pyrazolyl, is optionally substituted with 1, or 2, or 3         groups that are independently halogen, CF₃, or (C₁-C₄)alkyl.

In another aspect, the invention provides compounds of formula III-i, i.e., compounds according to formula III-h wherein

-   m is 2; -   heteroaryl is indolyl, benzothienyl, benzofuranyl, quinolinyl, or     imidazo[2,1-b]thiazolyl, wherein each is optionally substituted with     1, 2, or 3 groups that are independently halogen, C₁-C₆ alkyl,     phenyl, benzyl, phenyloxy, pyrazolyl, —SO₂-phenyl, CN, C₁-C₄     thioalkoxy, C₁-C₄ alkoxycarbonyl, —NR′R″, piperidinyl, wherein     -   the above phenyl groups are optionally substituted with 1, 2, 3,         or 4 groups that are independently halogen, C₁-C₆ alkyl, C₁-C₆         alkoxy, or CN;     -   the pyrazolyl, is optionally substituted with 1, or 2, or 3         groups that are independently halogen, CF₃, or (C₁-C₄)alkyl.

In another aspect, the invention provides compounds of formula III-i1, i.e., compounds according to formula III-b, wherein

-   R₁ is benzoimidazolyl(C₁-C₆ alkyl), benzooxazolyl(C₁-C₆ alkyl),     benzo[1,2,5]oxadiazolyl(C₁-C₆ alkyl), 1H-indazolyl(C₁-C₆ alkyl),     1H-benzotriazolyl(C₁-C₆ alkyl), furo[3,2-b]pyridinyl(C₁-C₆ alkyl),     1H-pyrazolo[3,4-b]pyridinyl(C₁-C₆ alkyl),     1H-pyrazolo[3,4-c]pyridinyl(C₁-C₆ alkyl), quinoxalinyl(C₁-C₆ alkyl),     or isoquinolinyl(C₁-C₆ alkyl),     -   wherein the cyclic portions of each of the above are optionally         substituted with 1, 2, or 3 groups that are independently         halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, CF₃, OCF₃, phenyl,         phenyl(C₁-C₆ alkyl), phenyloxy, pyrazolyl, imidazolyl, furanyl,         thienyl, morpholinyl, —SO₂-phenyl, —SO₂—(C₁-C₆ alkyl),         —S(O)_(x)—R₂₅, —(C₁-C₄ alkyl)-S(O)_(x)—R₂₅, CN, C₁-C₆         thioalkoxy, C₁-C₆ alkoxycarbonyl, pyridyl, piperidinyl,         piperazinyl, pyrrolidinyl, or tetrahydrofuranyl,         -   wherein the above phenyl groups are optionally substituted             with 1, 2, 3, or 4 groups that are independently halogen,             C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₄ haloalkyl, C₁-C₄             haloalkoxy, or CN;         -   wherein the above heteroaryl and heterocycloalkyl groups are             optionally substituted with 1, 2, or 3 groups that are             independently halogen, CF₃, (C₁-C₄)alkyl, C₁-C₆ thioalkoxy,             or C₁-C₄ alkoxy.

In another aspect, the invention provides compounds of formula III-i2, i.e., compounds according to formula III-i1, wherein R₁ is benzoimidazolyl(C₁-C₆ alkyl), benzooxazolyl(C₁-C₆ alkyl), benzo[1,2,5]oxadiazolyl(C₁-C₆ alkyl), 1H-indazolyl(C₁-C₆ alkyl), 1H-benzotriazolyl(C₁-C₆ alkyl), furo[3,2-b]pyridinyl(C₁-C₆ alkyl), 1H-pyrazolo[3,4-b]pyridinyl(C₁-C₆ alkyl), 1H-pyrazolo[3,4-c]pyridinyl(C₁-C₆ alkyl), quinoxalinyl(C₁-C₆ alkyl), or isoquinolinyl(C₁-C₆

-   wherein the cyclic portions of each of the above are optionally     substituted with 1, 2, or 3 groups that are independently halogen,     C₁-C₆ alkyl, C₁-C₆ alkoxy, CF₃, OCF₃, CN, C₁-C₆ thioalkoxy, or C₁-C₆     alkoxycarbonyl.

In another aspect, the invention provides compounds of formula III-i3, i.e., compounds according to formula III-b, wherein R₁ is benzoimidazolyl(C₁-C₆ alkyl), benzooxazolyl(C₁-C₆ alkyl), benzo[1,2,5]oxadiazolyl(C₁-C₆ alkyl), 1H-indazolyl(C₁-C₆ alkyl), 1H-benzotriazolyl(C₁-C₆ alkyl), furo[3,2-b]pyridinyl(C₁-C₆ alkyl), 1H-pyrazolo[3,4-b]pyridinyl(C₁-C₆ alkyl), 1H-pyrazolo[3,4-c]pyridinyl(C₁-C₆ alkyl), quinoxalinyl(C₁-C₆ alkyl), or isoquinolinyl(C₁-C₆ alkyl),

-   -   wherein the cyclic portions of each of the above are optionally         substituted with 1, 2, 3, 4, or 5 groups that are independently         halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, CF₃, OCF₃, —NR′R″, or         —C(O)—NR′R″, wherein     -   R′ is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl,         phenyl(C₁-C₄)alkyl, C₁-C₆ alkanoyl, phenyl(C₁-C₆)alkanoyl,         pyridyl(C₁-C₄)alkyl, pyrimidyl(C₁-C₄)alkyl,         pyridazyl(C₁-C₄)alkyl, pyrazinyl(C₁-C₄)alkyl,         thienyl(C₁-C₄)alkyl, oxazolyl(C₁-C₄)alkyl,         thiazolyl(C₁-C₄)alkyl, furanyl(C₁-C₄)alkyl,         piperidinyl(C₁-C₄)alkyl, —SO₂-alkyl, —SO₂-phenyl, —SO₂-pyridyl,         —SO₂-pyrimidyl, —SO₂-pyridazyl, —SO₂-pyrazinyl, —SO₂-thienyl,         —SO₂-oxazolyl, —SO₂-thiazolyl, —SO₂-furanyl,         pyridyl(C₁-C₆)alkanoyl, pyrimidyl(C₁-C₆)alkanoyl,         pyridazyl(C₁-C₆)alkanoyl, pyrazinyl(C₁-C₆)alkanoyl,         thienyl(C₁-C₆)alkanoyl, oxazolyl(C₁-C₆)alkanoyl,         thiazolyl(C₁-C₆)alkanoyl, or furanyl(C₁-C₆)alkanoyl, wherein the         alkyl portion of the alkyl and alkanoyl groups are optionally         substituted with halogen or C₁-C₆ alkoxy,         -   wherein the aryl, and heteroaryl groups are optionally             substituted with alkyl, alkoxy, halogen, haloalkyl,             haloalkoxy, and     -   R″ is H, or C₁-C₆ alkyl, wherein the alkyl group is optionally         substituted with halogen.

In another aspect, the invention provides compounds of formula III-i4, i.e., compounds according to formula III-i3, wherein R′ is H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, phenyl, phenyl(C₁-C₄)alkyl, C₁-C₄ alkanoyl, phenyl(C₁-C₄)alkanoyl, pyridyl(C₁-C₄)alkyl, pyrimidyl(C₁-C₄)alkyl, pyridazyl(C₁-C₄)alkyl, pyrazinyl(C₁-C₄)alkyl, thienyl(C₁-C₄)alkyl, oxazolyl(C₁-C₄)alkyl, thiazolyl(C₁-C₄)alkyl, furanyl(C₁-C₄)alkyl, piperidinyl(C₁-C₄)alkyl, —SO₂-alkyl, —SO₂-phenyl, pyridyl(C₁-C₆)alkanoyl, thienyl(C₁-C₄)alkanoyl, oxazolyl(C₁-C₄)alkanoyl, thiazolyl(C₁-C₄)alkanoyl, or furanyl(C₁-C₄)alkanoyl, wherein the alkyl portion of the alkyl and alkanoyl groups are optionally substituted with halogen or C₁-C₄ alkoxy, wherein the aryl, and heteroaryl groups are optionally substituted with alkyl, alkoxy, halogen, CF₃, OCF₃, and R″ is H, or C₁-C₄ alkyl, wherein the alkyl group is optionally substituted with halogen.

In another aspect, the invention provides compounds of formula III-i5, i.e., compounds according to formula III-i4, wherein R′ is H, C₁-C₆ alkyl, cyclopropyl, cyclohexyl, phenyl, benzyl, C₁-C₄ alkanoyl, phenyl(C₁-C₄)alkanoyl, pyridyl(C₁-C₄)alkyl, pyrimidyl(C₁-C₄)alkyl, pyrazinyl(C₁-C₄)alkyl, thienyl(C₁-C₄)alkyl, oxazolyl(C₁-C₄)alkyl, thiazolyl(C₁-C₄)alkyl, furanyl(C₁-C₄)alkyl, piperidinyl(C₁-C₄)alkyl, —SO₂-alkyl, —SO₂-phenyl, pyridyl(C₁-C₄)alkanoyl, thienyl(C₁-C₄)alkanoyl, wherein the alkyl portion of the alkyl and alkanoyl groups are optionally substituted with halogen or C₁-C₄ alkoxy, wherein the aryl, and heteroaryl groups are optionally substituted with alkyl, alkoxy, halogen, CF₃, OCF₃, and R″ is H, or C₁-C₄ alkyl.

In another aspect, the invention provides compounds of formula III-i6, i.e., compounds according to formula III-i5, wherein R′ is H, C₁-C₆ alkyl, cyclopropyl, cyclohexyl, phenyl, or benzyl, wherein the alkyl portion of the alkyl group is optionally substituted with halogen or C₁-C₄ alkoxy, and wherein the groups are optionally substituted with C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, CF₃, or OCF₃ and R″ is H, or C₁-C₄ alkyl.

In another aspect, the invention provides compounds of formula III-i7, i.e., compounds according to formula III-i5, wherein R′ is C₁-C₄ alkanoyl, phenyl(C₁-C₄)alkanoyl, pyridyl(C₁-C₄)alkyl, pyrimidyl(C₁-C₄)alkyl, pyrazinyl(C₁-C₄)alkyl, thienyl(C₁-C₄)alkyl, oxazolyl(C₁-C₄)alkyl, thiazolyl(C₁-C₄)alkyl, furanyl(C₁-C₄)alkyl, piperidinyl(C₁-C₄)alkyl, —SO₂-alkyl, —SO₂-phenyl, pyridyl(C₁-C₄)alkanoyl, thienyl(C₁-C₄)alkanoyl, wherein the alkyl portion of the alkyl and alkanoyl groups are optionally substituted with halogen or C₁-C₄ alkoxy, wherein the aryl, and heteroaryl groups are optionally substituted with alkyl, alkoxy, halogen, CF₃, OCF₃, and R″ is H, or C₁-C₄ alkyl.

In another aspect, the invention provides compounds of formula III-i8, i.e., compounds according to formula III-i5, wherein R′ is H, C₁-C₄ alkyl, C₁-C₄ alkanoyl, phenyl(C₁-C₄)alkanoyl, —SO₂-alkyl, —SO₂-phenyl, pyridyl(C₁-C₄)alkanoyl, orthienyl(C₁-C₄)alkanoyl, wherein the alkyl portion of the alkyl and alkanoyl groups are optionally substituted with halogen or C₁-C₄ alkoxy, wherein the aryl, and heteroaryl groups are optionally substituted with alkyl, alkoxy, halogen, CF₃, OCF₃, and R″ is H, or C₁-C₄ alkyl.

In another aspect, the invention provides compounds of formula III-i9, i.e., compounds according to formula III-i5, wherein R′ is H, C₁-C₄ alkyl, pyridyl(C₁-C₄)alkyl, pyrimidyl(C₁-C₄)alkyl, pyrazinyl(C₁-C₄)alkyl, thienyl(C₁-C₁)alkyl, oxazolyl(C₁-C₄)alkyl, thiazolyl(C₁-C₄)alkyl, furanyl(C₁-C₄)alkyl, piperidinyl(C₁-C₄)alkyl, —SO₂-alkyl, —SO₂-phenyl, pyridyl(C₁-C₄)alkanoyl, thienyl(C₁-C₄)alkanoyl, wherein the alkyl portion of the alkyl and alkanoyl groups are optionally substituted with halogen or C₁-C₄ alkoxy, wherein the aryl, and heteroaryl groups are optionally substituted with alkyl, alkoxy, halogen, CF₃, OCF₃, and R″ is H, or C₁-C₄ alkyl.

In another aspect, the invention provides compounds of formula III-i10, i.e., compounds according to any one of formulas III-i, III-i1, III-i2, III-i3, III-i4, III-i5, III-i6, III-i7, III-i8, or III-i9, wherein R₁₀, R₃₁, and R_(3′) are all H. Preferably, at least one of R₃ and R₄ is halogen. More preferably, n is 2 or 3. Still more preferably, n is 3.

In another aspect, the invention provides compounds of formula III-j, i.e., compounds according to formula I-a wherein

-   R₁ is phenyl(C₂-C₆ alkenyl) or naphthyl(C₂-C₆ alkenyl), wherein the     cyclic portion of each is optionally substituted with 1, 2, 3, 4, or     5 groups that are independently     -   C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, CF₃, OCF₃, thiazolyl,         oxazolyl, pyrazolyl, thiazolyl(C₁-C₆)alkoxy,         pyridyl(C₁-C₆)alkoxy, phenyl(C₁-C₄)alkoxy,         oxazolyl(C₁-C₄)alkoxy, pyrazolyl(C₁-C₄)alkoxy, phenyloxy, C₁-C₆         alkoxycarbonyl, —O—CH₂CH₂—O—, —O—CH₂—O—, —NHR′, —NR′R″,         morpholinyl, thiomorpholinyl, thiomorpholinyl S,S-dioxide,         piperidinyl, pyrrolidinyl, phenyl, CN, —SO₂-phenyl, —(C₁-C₄         alkyl)-SO₂-phenyl, OH, C₁-C₆ thioalkoxy, C₂-C₆ alkenyl,or         —O—SO₂-phenyl, wherein         -   the heteroaryl group is optionally substituted with 1, 2, or             3 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,             or halogen,         -   the heterocycloalkyl group is optionally substituted with             C₁-C₆ alkyl, C₁-C₆ alkoxy, or halogen,         -   the above phenyl groups are optionally substituted with 1,             2, 3, 4 or 5 groups that are independently halogen, C₁-C₆             alkyl, or C₁-C₄ alkoxy,         -   R′ is H, C₁-C₆ alkyl, or C₁-C₆ alkanoyl, wherein the alkyl             portion of the alkyl and alkanoyl groups are optionally             substituted with halogen, or C₁-C₆ alkoxy,         -   R″ is H or C₁-C₆ alkyl, wherein the alkyl group is             optionally substituted with halogen.

In another aspect, the invention provides compounds of formula III-k, i.e., compounds according to formula I-j wherein

-   R₃ is H, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or CN; -   R₄ is halogen, C₁-C₄ alkoxy, C₁-C₄ alkyl, CF₃, OCF₃, CN, —NHR′,     —NR′R″, or C₁-C₄ alkanoyl, -   R_(3′) is H, —SO₂—NR′R″, or halogen; or -   R₄ and R_(3′) and the carbons to which they are attached form a     benzo ring.

In another aspect, the invention provides compounds of formula III-l, i.e., compounds according to formula III-k wherein

-   R₁ is phenyl(C₂-C₆ alkenyl) wherein the cyclic portion is optionally     substituted with 1, 2, 3, 4, or 5 groups that are independently     -   C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, CF₃, OCF₃, thiazolyl,         oxazolyl, pyrazolyl, thiazolyl(C₁-C₄)alkoxy,         pyridyl(C₁-C₄)alkoxy, phenyl(C₁-C₄)alkoxy,         oxazolyl(C₁-C₄)alkoxy, pyrazolyl(C₁-C₄)alkoxy, phenyloxy, C₁-C₄         alkoxycarbonyl, —O—CH₂CH₂—O—, —O—CH₂—O—, morpholinyl, NH₂,         NH(C₁-C₄)alkyl, N(C₁-C₄)alkyl(C₁-C₄)alkyl, piperidinyl,         pyrrolidinyl, phenyl, CN, OH, C₁-C₄ thioalkoxy, C₂-C₆ alkenyl,         wherein         -   the heteroaryl group is optionally substituted with 1, 2, or             3 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,             or halogen,         -   the heterocycloalkyl group is optionally substituted with             C₁-C₆ alkyl, C₁-C₆ alkoxy, or halogen,     -   the above phenyl groups are optionally substituted with 1, 2, 3,         4 or 5 groups that are independently halogen, C₁-C₆ alkyl, or         C₁-C₄ alkoxy.

In another aspect, the invention provides compounds of formula III-m, i.e., compounds according to formula III-l wherein

-   R₂ is H, methyl, or benzyl; -   R₁₀ and R₁₁ are simultaneously H; and -   R₁ is phenyl(C₃-C₆ alkenyl) wherein the cyclic portion is optionally     substituted with 1, 2, 3, 4, or 5 groups that are independently     C₂-C₆ alkyl, C₁-C₆ alkoxy, halogen, CF₃, OCF₃, phenyl(C₁-C₄)alkoxy,     phenyloxy, C₁-C₄ alkoxycarbonyl, —O—CH₂CH₂—O—, —O—CH₂—O—, NH₂,     NH(C₁-C₄)alkyl, N(C₁-C₄)alkyl(C₁-C₄)alkyl, phenyl, CN, OH, C₁-C₄     thioalkoxy, C₂-C₆ alkenyl, wherein     -   the above phenyl groups are optionally substituted with 1, 2, or         3 groups that are independently halogen, C₁-C₄ alkyl, or C₁-C₄         alkoxy.

In another aspect, the invention provides compounds of formula III-n, i.e., compounds according to formula III-m wherein

-   R₂ is H; R₃ is H, halogen, methyl, ethyl, methoxy, ethoxy, CF₃, or     CN; -   R₄ is halogen, C₁-C₄ alkoxy, C₁-C₄ alkyl, CF₃, OCF₃, CN, —NHR′,     —NR′R″, or C₁-C₄ alkanoyl, -   R_(3′) is H, or halogen; or -   R₄ and R_(3′) and the carbons to which they are attached form a     benzo ring.

In another aspect, the invention provides compounds of formula III-o, i.e., compounds according to formula III-n wherein R₄ is halogen; and R₃ is H, halogen, methyl or methoxy. In another aspect, R₄ is Cl. In another aspect, R₃ is H or halogen. In still another aspect, R₄ is Cl, and R₃ is H or halogen.

In another aspect, the invention provides compounds of formula III-p, i.e., compounds according to formula III-n wherein R₄ and R_(3′) and the carbons to which they are attached form a benzo ring.

In another aspect, the invention provides compounds of formula III-q, i.e., compounds according to any one of formulas III-j, III-k, III-l, III-m, III-o, or III-p wherein

-   n is 1. In another aspect, n is 2. In still another aspect, n is 3.

In yet another aspect, the invention provides compounds of formula I-b, i.e., compounds of formula I wherein

-   R₂ is H, methyl, or benzyl; -   R₁₀ and R₁₁ are simultaneously H; -   R₃ is H, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or CN, -   R₄ is halogen, C₁-C₄ alkoxy, C₁-C₄ alkyl, CF₃, OCF₃, CN, —NHR′,     —NR′R″, or C₁-C₄ alkanoyl, -   R_(3′) is H, —SO₂—NR′R″, or halogen; or -   R₄ and R_(3′) and the carbons to which they are attached form a     benzo ring.

In another aspect, the invention provides compounds of formula i.e., compounds of formula I-b wherein

-   R₁ is C₁-C₁₄ alkyl, C₂-C₁₆ alkenyl, or C₂-C₆ alkynyl, each of which     is optionally substituted with 1 or 2 groups that are independently     OH, halogen, C₁-C₆ alkoxy, phenyl, naphthyl, phenyl(C₁-C₄)alkoxy,     phenyloxy, phenyl(C₁-C₄)alkyl, pyridyl, thienyl, —CO₂—(C₁-C₆ alkyl),     —NR′R″, C₁-C₆ thioalkoxy, OH, —N(R₁₆)C(O)—R₁₇, —C(O)NR₃₀R₃₁,     —NH—S(O)_(x)—R₂₅, —N(C₁-C₆ alkyl)-S(O)_(x)—R₂₅, CN, or —S(O)     _(x)—R₂₅,     -   wherein the above phenyl and naphthyl groups are optionally         substituted with 1, 2, or 3 groups that are independently OH,         C₁-C₆ alkoxy, C₁-C₆ alkyl, or halogen;     -   x is 0, 1, or 2;     -   R₁₆ is H or C₁-C₆ alkyl;     -   R₁₇ is C₁-C₆ alkyl, phenyl, pyridyl, pyrimidyl, pyridazyl,         pyrazinyl, thienyl, oxazolyl, thiazolyl, furanyl, C₁-C₆ alkoxy,         OH, phenyloxy, pyridyloxy, pyrimidyloxy, pyridazyloxy,         pyrazinyloxy, thienyloxy, oxazolyloxy, thiazolyloxy, furanyloxy,         phenyl(C₁-C₆)alkoxy, or —NR₁₈R₁₉;     -   R₃₉ and R₁₉ are independently H, C₁-C₆ alkyl, phenyl, pyridyl,         piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,         thiomorpholinyl 1,1-dioxide, tetrahydro-thiopyranyl 1,1-dioxide,         or phenyl(C₁-C₄)alkyl;     -   R₂₅ is C₁-C₆ alkyl, OH, NR₂₆R₂₇;     -   R₂₆ and R₂₇ are independently H, C₁-C₆ alkyl, phenyl(C₁-C₄         alkyl), phenyl, naphthyl or pyridyl, pyrimidyl, thienyl, furanyl         or quinolinyl; or     -   R₂₆, R₂₇ and the nitrogen to which they are attached form a         heterocycloalkyl ring, which contains 2 to 7 carbon atoms, and     -   R₃₀ and R₃₁ are independently H, C₁-C₆ alkyl, phenyl, benzyl,         pyridyl, thiazolyl, oxazolyl, or indolyl, or     -   R₃₀, R₃₁, and the nitrogen to which they are attached form a         azepanyl, piperidinyl, pyrrolidinyl, morpholinyl,         thiomorpholinyl, or thiomorpholinyl 1,1-dioxide.

In another aspect, the invention provides compounds of formula I-d, i.e., compounds of formula I-c wherein R₄ is halogen; and R₃ is H, halogen, methyl or methoxy. In another aspect, R₄ is Cl. In another aspect, R₃ is H or halogen. In still another aspect, R₄ is Cl, and R₃ is H or halogen.

In another aspect, the invention provides compounds of formula I-e, i.e., compounds of formula I-c wherein R₄ and R_(3′) and the carbons to which they are attached form a benzo ring. In another aspect, R₄ and R_(3′) and the carbons to which they are attached form a benzo ring and R₃ is H, halogen, methyl or methoxy.

In yet another aspect, the invention provides compounds of formula I-f, i.e., compounds according to any one of formulas I-c, I-d, or I-e wherein

-   R₁ is C₁-C₁₄ alkyl (in another aspect, C₁-C₁₀ alkyl, in still     another aspect, C₁-C₈ alkyl, in yet still another aspect, C₁-C₆     alkyl), which is optionally substituted with 1 or 2 groups that are     independently OH, halogen, C₁-C₆ alkoxy, phenyl, naphthyl,     phenyl(C₁-C₄)alkoxy, phenyloxy, —CO₂—(C₁-C₄ alkyl), —NR′R″, C₁-C₄     thioalkoxy, OH, —C(O)NR₃₀R₃₁, —N(R₁₆)C(O)—R₁₇, —NH—S(O)_(x)—R—₂₅,     —N(C₁-C₆ alkyl)-S(O)_(x)—R₂₅, CN, or —S(O)_(x)—R₂₅;     -   wherein the above phenyl and naphthyl groups are optionally         substituted with 1, 2, or 3 groups that are independently OH,         C₁-C₄ alkoxy, C₁-C₄ alkyl, or halogen     -   x is 0, 1, or 2;     -   R₂₅ is C₁-C₆ alkyl, OH, NR₂₆R₂₇;     -   R₂₆ and R₂₇ are independently H, C₁-C₆ alkyl, phenyl(C₁-C₄         alkyl), phenyl, naphthyl pyridyl, pyrimidyl, thienyl, furanyl or         quinolinyl; or     -   R₂₆, R₂₇ and the nitrogen to which they are attached form a         heterocycloalkyl ring selected from piperidinyl, morpholinyl,         pyrrolidinyl, and piperazinyl.

In yet another aspect, the invention provides compounds of formula I-g, i.e., compounds according to any one of formulas I-d, I-e, or I-f wherein R₁ is

wherein

-   m is 0, 1, 2, 3, 4, 5, or 6; -   R₂₀ is H or methyl; -   Y is halogen, C₁-C₄ alkoxy, benzyloxy, phenyloxy, —CO₂—(C₁-C₄     alkyl), —NR′R″, C₁-C₄ thioalkoxy, OH, —C(O)NR₃₀R₃₁, —N(R₁₆)C(O)—R₁₇,     or —S(O)_(x)—R₂₅;     -   wherein the above phenyl groups are optionally substituted with         1, 2, or 3 groups that are independently OH, C₁-C₄ alkoxy, C₁-C₄         alkyl, or halogen;     -   x is 0, 1, or 2;     -   R₂₅ is C₁-C₆ alkyl, OH, NR₂₆R₂₇;     -   R₂₆ and R₂₇ are independently H, C₁-C₆ alkyl, phenyl(C₁-C₄         alkyl), phenyl, naphthyl, pyridyl, pyrimidyl, thienyl, or         furanyl; or     -   R₂₆, R₂₇ and the nitrogen to which they are attached form a         heterocycloalkyl ring selected from piperidinyl, morpholinyl,         pyrrolidinyl, and piperazinyl.

In still another aspect, the invention provides compounds of formula I-G1, i.e., compounds of formula I-G wherein Y is —CO₂—(C₁-C₄ alkyl).

In another aspect, the invention provides compounds of formula I-h, i.e., compounds according formula I-g wherein

-   R₂₆ and R₂₇ are independently H, C₁-C₆ alkyl, phenyl(C₁-C₄ alkyl),     phenyl, naphthyl, pyridyl, pyrimidyl, thienyl, or furanyl.

In another aspect, the invention provides compounds of formula I-i, i.e., compounds according formula I-g, wherein

-   R₂₆, R₂, and the nitrogen to which they are attached form a     heterocycloalkyl ring selected from piperidinyl, morpholinyl,     pyrrolidinyl, and piperazinyl.

In another aspect, the invention provides compounds of formula I-j, i.e., compounds according formula I-g wherein

-   R₃₀ and R₃₁ are independently H, C₁-C₆ alkyl, phenyl, benzyl,     pyridyl, thiazolyl, oxazolyl, or indolyl.

In another aspect, the invention provides compounds of formula I-k, i.e., compounds according formula I-g wherein

-   R₃₀, R₃₁, and the nitrogen to which they are attached form a     azepanyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,     or thiomorpholinyl 1,1-dioxide.

In another aspect, the invention provides compounds of formula I-l, i.e., compounds according to any one of formulas I-c, I-d, E-e wherein

-   R₁ is C₂-C₁₆ alkenyl which is optionally substituted with 1 or 2     groups that are independently OH, halogen, C₁-C₆ alkoxy,     phenyl(C₁-C₄)alkoxy, phenyloxy, phenyl(C₁-C₄)alkyl, pyridyl,     pyrimidyl, furanyl, thienyl, indolyl, —CO₂—(C₁-C₄ alkyl), —NR′R″,     C₁-C₄ thioalkoxy, or OH,     -   wherein the above phenyl and naphthyl groups are optionally         substituted with 1, 2, or 3 groups that are independently OH,         C₁-C₄ alkoxy, C₁-C₄ alkyl, or halogen.

In another aspect, the invention provides compounds of formula I-m, i.e., compounds of formula I-l wherein

-   R₁ is

wherein

-   R₂₁ and R₂₂ are independently H or C₁-C₆ alkyl; -   R₂₃ is H, —C(O)NR₃₀R₃₁, —CO₂—(C₁-C₄ alkyl), C₁-C₆ alkyl, phenyl,     naphthyl, benzyl, pyridyl, pyrimidyl, furanyl, or thienyl;     -   R₃₀ and R₃₁ are independently H, C₁-C₆ alkyl, phenyl, benzyl,         pyridyl, thiazolyl, oxazolyl, or indolyl, or     -   R₃₀, R₃₁, and the nitrogen to which they are attached form a         azepanyl, piperidinyl, pyrrolidinyl, morpholinyl,         thiomorpholinyl, or thiomorpholinyl 1,1-dioxide.

In another aspect, the invention provides compounds of formula I-n, i.e., compounds of formula I-m wherein

-   R₁ is

In another aspect, the invention provides compounds of formula I-o, i.e., compounds of formula I-m wherein

-   R₁ is

In another aspect, the invention provides compounds of formula I-p, i.e., compounds of formula I-m wherein

-   R₁ is

In still another aspect, the invention provides compounds of formula I-q, i.e., compounds according to any one of formulas I-m, I-n, I-o, or I-p wherein R₂₃ is —C(O)NR₃₀R₃₁.

In yet another aspect, the invention provides compounds of formula I-q1, i.e., compounds of formula I-p wherein R₂₃ is —CO₂—(C₁-C₄ alkyl).

In still another aspect, the invention provides compounds of formula I-r, i.e., compounds according to any one of formulas I-c, I-d, or I-e wherein

-   R₁ is C₂-C₆ alkynyl, which is optionally substituted with 1 or 2     groups that are independently halogen, C₁-C₆ alkoxy, phenyl,     naphthyl, phenyl(C₁-C₄)alkoxy, phenyloxy, —CO₂—(C₁-C₄ alkyl),     —NR′R″, C₁-C₄ thioalkoxy, or OH,     -   wherein the above phenyl and naphthyl groups are optionally         substituted with 1, 2, or 3 groups that are independently OH,         C₁-C₄ alkoxy, C₁-C₄ alkyl, or halogen.

In another aspect, the invention provides compounds of formula I-s, i.e., compounds of formula I-r wherein

-   R₁ is

wherein

-   m is 0, 1, or 2; -   R₂₁ is H or methyl; -   R₂₄ is H, halogen, C₁-C₆ alkoxy, phenyl, naphthyl,     phenyl(C₁-C₄)alkoxy, phenyloxy, —CO₂—(C₁-C₄ alkyl), —NR′R″, C₁-C₄     thioalkoxy, or OH, wherein the above phenyl and naphthyl groups are     optionally substituted with 1, 2, or 3 groups that are independently     OH, C₁-C₄ alkoxy, C₁-C₄ alkyl, or halogen.

In another aspect, the invention provides compounds of formula I-t, i.e., compounds of formula I-m wherein

-   R₁ is

wherein

-   m is 0, 1, or 2; -   R₂₁ is H or methyl; -   R₂₄ is H, halogen, C₁-C₆ alkoxy, phenyl, naphthyl,     phenyl(C₁-C₄)alkoxy, phenyloxy, —CO₂—(C₁-C₄ alkyl), —NR′R″, C₁-C₄     thioalkoxy, or OH, wherein the above phenyl and naphthyl groups are     optionally substituted with 1, 2, or 3 groups that are independently     OH, C₁-C₄ alkoxy, C₁-C₄ alkyl, or halogen.

In another aspect, the invention provides compounds of formula I-u, i.e., compounds according to any one of formulas I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-j, I-k, I-l, I-m, I-n, I-o, I-p, I-q, or I-r wherein n is 1. In another aspect, n is 2. In still another aspect, n is 3.

In another aspect, the invention provides compounds of formula I-v, i.e., compounds of formula I-b wherein

-   R₁ is C₃-C₇ cycloalkyl(C₁-C₄ alkyl) wherein the cyclic portion is     optionally substituted with 1, 2, 3, 4, or 5 groups that are     independently halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxycarbonyl, CO₂H,     or C₁-C₆ alkoxy.

In another aspect, the invention provides compounds of formula I-w, i.e., compounds of formula I-v wherein R₄ is halogen; and R₃ is H, halogen, methyl or methoxy. In another aspect, R₄ is Cl. In another aspect, R₃ is H or halogen. In still another aspect, R₄ is Cl, and R₃ is H or halogen.

In another aspect, the invention provides compounds of formula I-x, i.e., compounds of formula I-v wherein R₄ and R_(3′) and the carbons to which they are attached form a benzo ring. In another aspect, R₄ and R_(3′) and the carbons to which they are attached form a benzo ring and R₃ is H, halogen, methyl or methoxy.

In another aspect, the invention provides compounds of formula I-y, i.e., compounds according to any one of formulas I-w or I-x wherein

-   R₁ is cyclopropyl(C₁-C₄ alkyl), cyclopentyl(C₁-C₄ alkyl), or     cyclohexyl(C₁-C₄ alkyl), wherein the cyclic portion is optionally     substituted with 1, 2, or 3 groups that are independently halogen,     C₁-C₄ alkyl, OH, C₁-C₄ alkoxycarbonyl,or C₁-C₄ alkoxy.

In another aspect, the invention provides compounds of formula I-z, i.e., compounds according to any one of formulas I-v, I-w, or I-x,

-   R₁ is of the formula:

wherein

-   m is 0, 1, 2, or 3; -   R₂₀ is H or methyl; and -   cycloalkyl is C₃-C₇ cycloalkyl wherein the cyclic portion is     optionally substituted with 1, 2, 3, 4, or 5 groups that are     independently halogen, C₁-C₆ alkyl, OH, C₁-C₄ alkoxycarbonyl, or     C₁-C₆ alkoxy.

In another aspect, the invention provides compounds of formula I-aa, i.e., compounds formula I-z wherein

-   cycloalkyl is cyclopropyl, cyclopentyl, or cyclohexyl, wherein the     cyclic portion is optionally substituted with 1, 2, or 3 groups that     are independently halogen, C₁-C₄ alkyl, OH, C₁-C₄ alkoxycarbonyl, or     C₁-C₄ alkoxy.

In another aspect, the invention provides compounds of formula I-bb, i.e., compounds according to any one of formulas I-v, I-w, I-x, I-y, I-z, or I-aa wherein n is 1. In another aspect, n is 2. In still another aspect, n is 3.

In yet another aspect, the invention provides compounds of formula I-bb1, i.e., compounds of formula I-bb wherein cycloalkyl is cyclopropyl, which is optionally substituted as described above.

In yet another aspect, the invention provides compounds of formula I-bb1, i.e., compounds of formula I-bb wherein cycloalkyl is cyclopentyl, which is optionally substituted as described above.

In yet another aspect, the invention provides compounds of formula I-bb3, i.e., compounds of formula I-bb wherein cycloalkyl is cyclohexyl, which is optionally substituted as described above.

In another aspect, the invention provides compounds of formula I-cc, i.e., compounds of any one of formulas I-bb, I-bb1, I-bb2, or I-bb3, wherein m is 0 or 1.

In another aspect, the invention provides compounds of formula I-cc1, i.e., compounds of any one of formulas I-bb, I-bb1, I-bb2, or I-bb3, wherein m is 1 or 2.

In another aspect, the invention provides compounds of formula I-dd, i.e., compounds of formula I-b wherein

-   R₁ is 4-oxo-4H-chromen-3-yl(C₁-C₄ alkyl), 2H-chromen-3-yl(C₁-C₄     alkyl), pyrrolidinonyl dione(C₁-C₄ alkyl), isoindol-2-yl dione(C₁-C₄     alkyl), 1,3-dioxolan-2-yl(C₁-C₄ alkyl), dioxanyl(C₁-C₄ alkyl), or     tetrahydropyran-2-yl(C₁-C₄ alkyl), wherein the cyclic portion of     each is optionally substituted with 1, 2, 3, 4, or 5 groups that are     independently C₁-C₄ alkyl, C₁-C₄ alkoxy, or halogen; and -   R₂ is H.

In another aspect, the invention provides compounds of formula I-ee, i.e., compounds of formula I-dd wherein R₄ is halogen; and R₃ is H, halogen, methyl or methoxy. In another aspect, R₄ is Cl. In another aspect, R₃ is H or halogen. In still another aspect, R₄ is Cl, and R₃ is H or halogen.

In another aspect, the invention provides compounds of formula I-ff, i.e., compounds of formula I-dd wherein R₄ and R_(3′) and the carbons to which they are attached form a benzo ring. In another aspect, R₄ and R_(3′) and the carbons to which they are attached form a benzo ring and R₃ is H, halogen, methyl or methoxy.

In another aspect, the invention provides compounds of formula I-gg, i.e., compounds according to any one of formulas I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-j, I-k, or I-l wherein n is 1. In another aspect, n is 2. In still another aspect, n is 3.

In another aspect, the invention provides compounds of formula I-hh, i.e., compounds of formula I-f wherein R₁ is of the formula:

wherein

-   m is 0, 1, 2, or 3; -   R₂₀ is H or methyl; and -   heterocycloalkyl is 4-oxo-4H-chromen-3-yl, 2H-chromen-3-yl,     pyrrolidinonyl dione, isoindol-2-yl dione, 1,3-dioxolan-2-yl,     dioxanyl, or tetrahydropyran-2-yl, wherein the cyclic portion of     each is optionally substituted with 1, 2, 3, 4, or 5 groups that are     independently C₁-C₄ alkyl, C₁-C₄ alkoxy, or halogen.

In another aspect, the invention provides compounds of formula I-ii, i.e., compounds of formula wherein m is 0 or 1. In another aspect, m is 0 or 1 and heterocycloalkyl is isoindol-2-yl dione.

In another aspect, the invention provides compounds of formula I-ii1, i.e., compounds of formula I-g wherein m is 1 or 2. In another aspect, m is 1 or 2 and heterocycloalkyl is isoindol-2-yl dione.

In another aspect, the invention provides compounds of formula I-ii2, i.e., compounds of formula I-b, wherein R₁ is 3-oxo-1,3-dihydro-benzo[c]isoxazolyl(C₁-C₄ alkyl), 2-oxo-2,3-dihydro-1H-benzoimidazolyl(C₁-C₄ alkyl), 3-oxo-3,4-dihydro-1H-2-oxa-3lambda4-thia-1,4-diaza-naphthyl(C₁-C₄ alkyl), 3,3-dimethyl-3H-indazolyl(C₁-C₄ alkyl), or piperidinyl(C₁-C₄ alkyl), wherein the cyclic portion of each is optionally substituted with 1, 2, or 3 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, OCF₃, phenyl, phenyl(C₁-C₄ alkyl), phenyloxy, pyrazolyl, imidazolyl, furanyl, thienyl, morpholinyl, —SO₂-phenyl, —SO₂—(C₁-C₆ alkyl), —S(O)_(x)—R₂₅, alkyl)-S(O)_(x)—R₂₅, CN, C₁-C₄ thioalkoxy, C₁-C₄ alkoxycarbonyl, —NR′R″, —C(O)—NR′R″, pyridyl, piperidinyl, piperazinyl, pyrrolidinyl, or tetrahydrofuranyl, wherein the above phenyl groups are optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, or CN; wherein the above heteroaryl and heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, CF₃, (C₁-C₄)alkyl, C₁-C₆ thioalkoxy, or C₁-C₄ alkoxy.

In another aspect, the invention provides compounds of formula I-ii3, i.e., compounds of formula I-ii2, wherein R₁ is R₁ is 3-oxo-1,3-dihydro-benzo[c]isoxazolyl(C₁-C₂ alkyl), 2-oxo-2,3-dihydro-1H-benzoimidazolyl(C₁-C₂ alkyl), 3-oxo-3,4-dihydro-1H-2-oxa-3lambda4-thia-1,4-diaza-naphthyl(C₁-C₂ alkyl), or 3,3-dimethyl-3H-indazolyl(C₁-C₂ alkyl).

In another aspect, the invention provides compounds of formula I-ii4, i.e., compounds of formula I-ii3, wherein R₁ is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, phenyl(C₁-C₄)alkyl, C₁-C₆ alkanoyl, phenyl(C₁-C₆)alkanoyl, pyridyl(C₁-C₄)alkyl, pyrimidyl(C₁-C₄)alkyl, pyridazyl(C₁-C₄)alkyl, pyrazinyl(C₁-C₄)alkyl, thienyl(C₁-C₄)alkyl, oxazolyl(C₁-C₄)alkyl, thiazolyl(C₁-C₄)alkyl, furanyl(C₁-C₄)alkyl, piperidinyl(C₁-C₄)alkyl, —SO₂-alkyl, —SO₂-phenyl, —SO₂-pyridyl, —SO₂-pyrimidyl, —SO₂-pyridazyl, —SO₂-pyrazinyl, —SO₂-thienyl, —SO₂-oxazolyl, —SO₂-thiazolyl, —SO₂-furanyl, pyridyl(C₁-C₆)alkanoyl, pyrimidyl(C₁-C₆)alkanoyl, pyridazyl(C₁-C₆)alkanoyl, pyrazinyl(C₁-C₆)alkanoyl, thienyl(C₁-C₆)alkanoyl, oxazolyl(C₁-C₆)alkanoyl, thiazolyl(C₁-C₆)alkanoyl, or furanyl(C₁-C₆)alkanoyl, wherein the alkyl portion of the alkyl and alkanoyl groups are optionally substituted with halogen or C₁-C₆ alkoxy, wherein the aryl, and heteroaryl groups are optionally substituted with alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, and R″ is H, or C₁-C₆ alkyl, wherein the alkyl group is optionally substituted with halogen.

In another aspect, the invention provides compounds of formula I-ii5, i.e., compounds of formula I-ii4, wherein R′ is H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, phenyl, phenyl(C₁-C₄)alkyl, C₁-C₄ alkanoyl, phenyl(C₁-C₄)alkanoyl, pyridyl(C₁-C₄)alkyl, pyrimidyl(C₁-C₄)alkyl, pyridazyl(C₁-C₄)alkyl, pyrazinyl(C₁-C₄)alkyl, thienyl(C₁-C₄)alkyl, oxazolyl(C₁-C₄)alkyl, thiazolyl(C₁-C₄)alkyl, furanyl(C₁-C₄)alkyl, piperidinyl(C₁-C₄)alkyl, —SO₂-alkyl, —SO₂-phenyl, pyridyl(C₁-C₆)alkanoyl, thienyl(C₁-C₄)alkanoyl, oxazolyl(C₁-C₄)alkanoyl, thiazolyl(C₁-C₄)alkanoyl, or furanyl(C₁-C₄)alkanoyl, wherein the alkyl portion of the alkyl and alkanoyl groups are optionally substituted with halogen or C₁-C₄ alkoxy, wherein the aryl, and heteroaryl groups are optionally substituted with alkyl, alkoxy, halogen, CF₃, OCF₃, and R″ is H, or C₁-C₄ alkyl, wherein the alkyl group is optionally substituted with halogen.

In another aspect, the invention provides compounds of formula I-ii5, i.e., compounds of formula I-ii4, wherein R′ is H, C₁-C₆ alkyl, cyclopropyl, cyclohexyl, phenyl, benzyl, C₁-C₄ alkanoyl, phenyl(C₁-C₄)alkanoyl, pyridyl(C₁-C₄)alkyl, pyrimidyl(C₁-C₄)alkyl, pyrazinyl(C₁-C₄)alkyl, thienyl(C₁-C₄)alkyl, oxazolyl(C₁-C₄)alkyl, thiazolyl(C₁-C₄)alkyl, furanyl(C₁-C₄)alkyl, piperidinyl(C₁-C₄)alkyl, —SO₂-alkyl, —SO₂-phenyl, pyridyl(C₁-C₄)alkanoyl, thienyl(C₁-C₄)alkanoyl, wherein the alkyl portion of the alkyl and alkanoyl groups are optionally substituted with halogen or C₁-C₄ alkoxy, wherein the aryl, and heteroaryl groups are optionally substituted with alkyl, alkoxy, halogen, CF₃, OCF₃, and R″ is H, or C₁-C₄ alkyl.

In another aspect, the invention provides compounds of formula I-ii6, i.e., compounds of formula I-ii5, wherein R′ is R′ is H, C₁-C₆ alkyl, cyclopropyl, cyclohexyl, phenyl, or benzyl, wherein the alkyl portion of the alkyl group is optionally substituted with halogen or C₁-C₄ alkoxy, and wherein the groups are optionally substituted with C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, CF₃, or OCF₃ and R″ is H, or C₁-C₄ alkyl.

In another aspect, the invention provides compounds of formula I-ii7, i.e., compounds of formula I-ii5, wherein R′ is C₁-C₄ alkanoyl, phenyl(C₁-C₄)alkanoyl, pyridyl(C₁-C₄)alkyl, pyrimidyl(C₁-C₄)alkyl, pyrazinyl(C₁-C₄)alkyl, thienyl(C₁-C₄)alkyl, oxazolyl(C₁-C₄)alkyl, thiazolyl(C₁-C₄)alkyl, furanyl(C₁-C₄)alkyl, piperidinyl(C₁-C₄)alkyl, —SO₂-alkyl, —SO₂-phenyl, pyridyl(C₁-C₄)alkanoyl, thienyl(C₁-C₄)alkanoyl, wherein the alkyl portion of the alkyl and alkanoyl groups are optionally substituted with halogen or C₁-C₄ alkoxy, wherein the aryl, and heteroaryl groups are optionally substituted with alkyl, alkoxy, halogen, CF₃, OCF₃, and R″ is H, or C₁-C₄ alkyl.

In another aspect, the invention provides compounds of formula I-ii8, i.e., compounds of formula I-ii5, wherein R′ is H, C₁-C₄ alkyl, C₁-C₄ alkanoyl, phenyl(C₁-C₄)alkanoyl, —SO₂-alkyl, —SO₂-phenyl, pyridyl(C₁-C₄)alkanoyl, or thienyl(C₁-C₄)alkanoyl, wherein the alkyl portion of the alkyl and alkanoyl groups are optionally substituted with halogen or C₁-C₄ alkoxy, wherein the aryl, and heteroaryl groups are optionally substituted with alkyl, alkoxy, halogen, CF₃, OCF₃, and R″ is H, or C₁-C₄ alkyl.

In another aspect, the invention provides compounds of formula I-ii9, i.e., compounds of formula I-ii5, wherein R′ is R′ is H, C₁-C₄ alkyl, pyridyl(C₁-C₄)alkyl, pyrimidyl(C₁-C₄)alkyl, pyrazinyl(C₁-C₄)alkyl, thienyl(C₁-C₄)alkyl, oxazolyl(C₁-C₄)alkyl, thiazolyl(C₁-C₄)alkyl, furanyl(C₁-C₄)alkyl, piperidinyl(C₁-C₄)alkyl, —SO₂-alkyl, —SO₂-phenyl, pyridyl(C₁-C₄)alkanoyl, thienyl(C₁-C₄)alkanoyl, wherein the alkyl portion of the alkyl and alkanoyl groups are optionally substituted with halogen or C₁-C₄ alkoxy, wherein the aryl, and heteroaryl groups are optionally substituted with alkyl, alkoxy, halogen, CF₃, OCF₃, and R″ is H, or C₁-C₄ alkyl.

In another aspect, the invention provides compounds of formula I-ii10, i.e., compounds according to any one of formulas I-ii1, I-ii2, I-ii3, I-ii4, I-ii5, I-ii6, I-ii7, I-ii8, or I-ii9, wherein R₁₀, R₁₁, and R_(3′) are all H. Preferably, at least one of R₃ and R₄ is halogen. More preferably, n is 2 or 3. Still more preferably, n is 3.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of formula I and at least one pharmaceutically acceptable carrier, solvent, adjuvant and/or excipient.

Other preferred compounds of formula II, include those of formula X:

In one aspect, the invention provides compounds of formula X-a, i.e., compounds of formula X, wherein

-   R₆ and R₅ together with the carbon atoms to which they are attached     form a benzo group; or -   R₆ and R₇ together represent —O—CH₂—O—, or —O—CH₂CH₂—O—; or -   R₇ and R₈ together with the carbon atoms to which they are attached     form a benzo group; or -   R₈ is H, C₁-C₄ alkyl optionally substituted with —SO₂-phenyl,     halogen, CF₃, C₁-C₄ alkoxy (in one aspect, methoxy or ethoxy),     morpholin-4-yl, phenyl, —O—(CH₂)—C(O)O—(CH₂CH₃), or cyano; -   R₆ is H, F, Cl, Br, I, CF₃, C₁-C₄ alkoxy, C₁-C₄ alkoxycarbonyl, CN,     OCF₃, C₁-C₄ alkyl (in one aspect, methyl or tert-butyl), —O-phenyl     wherein the phenyl group is optionally substituted with F, C₂-C₃     alkenyl, methoxycarbonyl, or benzyloxy; -   R₇ is H, methoxycarbonyl, methoxy, ethoxy, isopropoxy, ethoxy     substituted with thiazol-5-yl, wherein the thiazolyl ring is     substituted with methyl, —SCH₃, methyl, isopropyl, tert-butyl,     isobutyl, F, Br, Cl, CF₃, OCF₃, cyano, N(CH₃)₂, N(C₂ alkyl     substituted with Cl) (C₂ alkyl substituted with Cl), phenyl, phenyl     substituted with methyl, benzyloxy, NO₂, —S(O)—C₁-C₆ alkyl,     —SO₂-C₁-C₆ alkyl, NH₂, NH (C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆     alkyl), —N(R₁₆)C(O)R₁₇, —C(O)NR₃₀R₃₁, C₁-C₂ haloalkyl, phenyloxy,     —O—SO₂-(4-chlorophenyl), —NH—C(O)—CH₃, —O—C(O)—CH₃, thiazolyl     substituted with tert-butyl, or OH; -   R₈ is H, halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl; -   R₉ is H, C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, or CN; and -   R₂₀ is H or methyl.

In another aspect, the invention provides compounds of formula X-a1, i.e., compounds of formula X wherein

-   R₄ and R_(3′) together form a phenyl group; and -   R₆ is selected from H, F, Cl, Br, I, CF₃, methoxycarbonyl, methoxy,     cyano, OCF₃, methyl, tert-butyl; -   R₇ is H, methoxycarbonyl, methoxy, ethoxy, isopropoxy, ethoxy     substituted with thiazol-5-yl, wherein the thiazolyl ring is     substituted with methyl, —SCH₃, methyl, isopropyl, tert-butyl,     isobutyl, F, Br, Cl, CF₃, OCF₃, cyano, N(CH₃)₂, N(C₂ alkyl     substituted with Cl) (C₂ alkyl substituted with Cl), phenyl, phenyl     substituted with methyl, benzyloxy, NO₂, —S(O)—C₁-C₆ alkyl,     —SO₂—C₁-C₆ alkyl, NH₂, NH (C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆     alkyl), —N(R₁₆)C(O)R₁₇, —C(O)NR₃₀R₃₁, phenyloxy,     —O—SO₂-(4-chlorophenyl), —NH—C(O)—CH₃, —O—C(O)—CH₃, thiazolyl     substituted with tert-butyl, —S(O)—C₁-C₆ alkyl, —SO₂—C₁-C₆ alkyl,     NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl) (C₁-C₆ alkyl), —N(R₁₆)C(O)R₁₇,     —C(O)NR₃₀R₃₁, C₁-C₂ haloalkyl, or OH.

In another aspect, the invention provides compounds of formula X-b, i.e., compounds of formula X-a wherein R₄ is H, F, Cl, Br, I, methoxy, tert-butyl, cyano, or —O-phenyl

-   -   wherein the phenyl group is optionally substituted with F, C₂         alkenyl, methoxycarbonyl, or benzyloxy.

In another aspect, the invention provides compounds of formula X-c, i.e., compounds according to any one of formulas X-a or X-b wherein

-   R₆, R₇ together are —O—CH₂—O—, or —O—CH₂CH₂—O—; or -   R₅ and R₆ together form a phenyl group.

In another aspect, the invention provides compounds of formula X-d, i.e., compounds of formula X-c wherein

-   R₆, R₇ together are —O—CH₂—O—, or —O—CH₂CH₂—O—.

In another aspect, the invention provides compounds of formula X-e, i.e., compounds of formula X-c wherein R₅ and R₆ together form a phenyl group.

In another aspect, the invention provides compounds of formula X-f, i.e., compounds of formula X wherein

-   R₅ is H, methyl, Cl, CF₃, methoxy, ethoxy, morpholin-4-yl, or     —O—(CH₂)—C(O) O—(CH₂CH₃); -   R₆ is H, F, Cl, Br, I, CF₃, methoxycarbonyl, methoxy, cyano, OCF₃,     methyl, or tert-butyl; -   R₇ is H, methoxycarbonyl, methoxy, ethoxy, isopropoxy, ethoxy     substituted with thiazol-5-yl, wherein the thiazolyl ring is     substituted with methyl, —SCH₃, methyl, isopropyl, tert-butyl,     isobutyl, F, Br, Cl, CF₃, OCF₃, cyano, N(CH₃)₂, N(C₂ alkyl     substituted with Cl) (C₂ alkyl substituted with Cl), phenyl, phenyl     substituted with methyl, benzyloxy, phenyloxy,     —O—SO₂-(4-chlorophenyl), —NH—C(O)—CH₃, —O—C(O)—CH₃, thiazolyl     substituted with tert-butyl, or OH; -   R₉ is H, F, Cl, Br, methoxy, tert-butyl, cyano, —O-phenyl wherein     the phenyl group is optionally substituted with halogen, C₂-C₄     alkenyl, C₁-C₄ alkoxycarbonyl, benzyloxy; -   R₉ is H, F, Cl, Br, methyl, —CH₂—SO₂-phenyl, cyano, methoxy, and     phenyl;

In another aspect, the invention provides compounds of formula X-g, i.e., compounds according to any one of formulas X, X-a, X-b, X-c, X-d, X-e, or X-f wherein R₄ is methyl, F, Cl or CF₃. In another aspect, R₃ is H. In still another aspect, R₃ ^(,) is also H. In yet another aspect, R₄ is F or Cl. In still another aspect, R₄ is Cl.

In another aspect, the invention provides compounds of formula X-h, i.e., compounds according to any one of formulas X, X-a, X-b, X-c, X-d, X-e, or X-f wherein R₄ is H. In another aspect, at least one of R₃ and R_(3′) is not H. In another aspect, neither R₃ nor R_(3′) is H.

In another aspect, the invention provides compounds of formula X-i, i.e., compounds according to any one of formulas X, X-a, X-b, X-c, X-d, X-e, or X-f wherein R₂ is H.

In another aspect, the invention provides compounds of formula X-j, i.e., compounds according to any one of formulas X, X-a, X-b, X-c, X-d, X-e, or X-f wherein R₂ is methyl.

In another aspect, the invention provides compounds of formula X-k, i.e., compounds of formula X wherein

-   R₅, R₆, R₈, and R₉ are H; -   R₇ is selected from methoxycarbonyl, methoxy, ethoxy, isopropoxy,     —SCH₃, methyl, isopropyl, tert-butyl, isobutyl, F, Br, Cl, CF₃,     OCF₃, cyano, N(CH₃)₂, N(C₂ alkyl substituted with Cl) (C₂ alkyl     substituted with Cl), phenyl, phenyl substituted with methyl,     benzyloxy, phenyloxy, —NH—C(O)—CH₃, —O—C(O)—CH₃, and thiazol-2-yl     substituted with tert-butyl.

In another aspect, the invention provides compounds of formula X-l, i.e., compounds of formula X-k wherein R₄ is methyl, F, Cl or CF₃. In another aspect, R₃ is H. In still another aspect, R_(3′) is also H. In yet still another aspect, R₂₀, and R₂ are also H. In yet another aspect, R₄ is F or Cl. In still another aspect, R₄ is Cl.

In another aspect, the invention provides compounds of formula X-m, i.e., compounds of formula X wherein R₄ is H. In another aspect, at least one of R₃ and R_(3′) is not H. In another aspect, neither of R₃ nor R_(3′) is H.

In another aspect, the invention provides compounds of formula X-n, i.e., compounds according to any one of formulas X-k, X-l, or X-m wherein R₇ is methoxycarbonyl, methoxy, ethoxy, isopropoxy, —SCH₃, methyl, isopropyl, tert-butyl, isobutyl, F, Br, Cl, CF₃, OCF₃, or cyano.

In another aspect, the invention provides compounds of formula X-o, i.e., compounds according to any one of formulas X-k, X-l, or X-m wherein R₇ is N(CH₃)₂, N(C₂ alkyl substituted with Cl) (C₂ alkyl substituted with Cl), phenyl, phenyl substituted with methyl, benzyloxy, phenyloxy, —NH—C(O)—CH₃, —O—C(O)—CH₃, or thiazol-2-yl substituted with tert-butyl.

In another aspect, the invention provides compounds of formula X-p, i.e., compounds according to formula X wherein R₅, R₆, R₇, and R₉ are H; R₉ is selected from F, Cl, Br, methyl, methyl substituted with —SO₂-phenyl, cyano, methoxy, and phenyl.

In another aspect, the invention provides compounds of formula X-q, i.e., compounds according to formula X-p wherein R₄ is methyl, F, Cl or CF₃. In another aspect, R₃ is H. In still another aspect, R_(3′) is also H. In yet still another aspect, R₂ is also H. In yet another aspect, R₄ is F or Cl. In still another aspect, R₄ is Cl.

In another aspect, the invention provides compounds of formula X-r, i.e., compounds according to formula X-p wherein R₄ is H. In another aspect, at least one of R₃ and R_(3′) is not H. In another aspect, neither of R₃ nor R_(3′) is H.

In another aspect, the invention provides compounds of formula X-s, i.e., compounds according to any one of formulas X-p, X-q, or X-r wherein R₅ is F, Cl, Br, methyl, or methoxy.

In another aspect, the invention provides compounds of formula X-t, i.e., compounds according to any one of formulas X-p, X-q, or X-r wherein R₅ is methyl substituted with —SO₂-phenyl, cyano, or phenyl.

In another aspect, the invention provides compounds of formula X-u, i.e., compounds of formula X wherein

-   R₆, R₇, R₈, and R₉ are H; and -   R₅ is ethoxy, morpholin-4-yl, or —O—(CH₂)—C(O)O—(CH₂CH₃).

In another aspect, the invention provides compounds of formula X-v, i.e., compounds of formula X-u wherein

-   R₄ is methyl, F, Cl or CF₃. In another aspect, R₃ is H. In still     another aspect, R_(3′) is also H. In yet still another aspect, R₂,     and R₂₀, are also H. In yet another aspect, R₄ is F or Cl. In still     another aspect, R₄ is Cl.

In another aspect, the invention provides compounds of formula X-w, i.e., compounds of formula X-u wherein R₄ is H. In another aspect, at least one of R₃ and R_(3′) is not H. In another aspect, neither of R₃ nor R_(3′) is H.

In another aspect, the invention provides compounds of formula X-x, i.e., compounds of formula X wherein

-   R₅, R₇, R₈, and R₉ are H; -   R₆ is Cl, Br, I, CF₃, methoxycarbonyl, methoxy, cyano, OCF₃, or     methyl.

In another aspect, the invention provides compounds of formula X-y, i.e., compounds of formula X-x wherein R₄ is methyl, F, Cl or CF₃. In another aspect, R₃ is H. In still another aspect, R_(3′) is also H. In yet still another aspect, R₂, and R₂₀, are also H. In yet another aspect, R₄ is F or Cl. In still another aspect, R₄ is Cl.

In another aspect, the invention provides compounds of formula X-z, i.e., compounds of formula X-x wherein

-   R₄ is H. In another aspect, at least one of R₃ and R_(3′) is not H.     In another aspect, neither of R₃ nor R_(3′) is H.

In another aspect, the invention provides compounds of formula X-aa, i.e., compounds according to any one of formulas

-   X-p, X-q, or X-r wherein -   R₆ is Cl, Br, I, CF₃, or OCF₃.

In another aspect, the invention provides compounds of formula X-bb, i.e., compounds according to any one of formulas X-p, X-q, or X-r wherein

-   R₆ is methoxycarbonyl, methoxy, cyano, or methyl.

In another aspect, the invention provides compounds of formula X-cc, i.e., compounds of formula X wherein

-   R₅, R₆, R₇, and R₉ are H; -   R₉ is —O-phenyl wherein the phenyl group is substituted with F, C₂     alkenyl, or benzyloxy.

In another aspect, the invention provides compounds of formula X-dd, i.e., compounds of formula X-cc wherein R₄ is methyl, F, Cl or CF₃. In another aspect, R₃ is H. In still another aspect, R_(3′) is also H. In yet still another aspect, R₂, R₂₀ are also H. In yet another aspect, R₄ is F or Cl. In still another aspect, R₄ is Cl.

In another aspect, the invention provides compounds of formula X-ee, i.e., compounds of formula X-cc wherein R₄ is H. In another aspect, at least one of R₃ and R_(3′) is not H. In another aspect, neither of R₃ nor R_(3′) is H.

Preferred compounds of formula X include those of formula XI:

wherein

-   R₄ is methyl, F, Cl or CF₃.

Other preferred compounds of formula X include those of formula

wherein

-   R₄ is methyl, F, Cl or CF₃.

In yet another aspect, the invention provides compounds of formula X-ff, i.e., compounds according to any one of formulas X-a, XI, or XII, wherein at least two of R₅, R₆, R₇, R₈ and R₉ are hydrogen.

In another aspect, the invention provides compounds of formula X-gg, i.e., compounds of formula X-ff, wherein one of R₅, R₆, R₇, R₈ and R₉ is —SCH₃, —S(O)CH₃, or —SO₂CH₃. More preferably, one of R₅, R₆, R₇, R₈, and R₉ is —SCH₃, —S(O)CH₃, or —SO₂CH₃ while the other four variables are all H.

In another aspect, the invention provides compounds of formula X-hh, i.e., compounds of formula X-ff, wherein one of R₅, R₆, R₇, R₈ and R₉ is

m wherein the alkyl is a divalent C₂-C₃ alkyl. Still more preferably one of R₅, R₆, R₇, R₈ and R₉ is

More preferably, four of R₅, R₆, R₇, R₈ and R₉ are H.

In another aspect, the invention provides compounds of formula X-ii, i.e., compounds of formula X-ff, wherein one of R₅, R₆, R₇, R₈ and R₉ is CN, —CO₂H, or mono halo C₁-C₂ alkyl (preferably —CH₂Cl). Still more preferably, four of R₅, R₆, R₇, R₈ and R₉ are H.

In another aspect, the invention provides compounds of formula X-jj, i.e., compounds of formula X-ff, wherein one of R₅, R₆, R₇, R₈ and R₉ is —N(R₁₆)C(O)R₁₇. More preferably, three of R₅, R₆, R₈ and R₉ are H. Still more preferably, R₇ is —N(R₁₆)C(O)R₁₇.

In another aspect, the invention provides compounds of formula X-kk, i.e., compounds of formula X-jj, wherein R₁₆ is H or C₁-C₄ alkyl (when R₁₆ is alkyl, it is preferably methyl or ethyl, more preferably it is methyl.)

In another aspect, the invention provides compounds of formula X-11, i.e., compounds of formula X-kk, wherein R₁₇ is C₁-C₄ alkoxy, phenyloxy, phenyl C₁-C₄ alkyl, phenyl, C₃-C₆ cycloalkyl, C₁-C₄ alkyl, pyridyl, pyrazinyl, pyrimidinyl, or —NR₁₈R₁₉, wherein R₁₈ and R₁₉ are independently H, C₁-C₆ alkyl, phenyl, naphthyl, pyridyl, pyrrolyl, piperazinyl, pyrimidinyl, furanyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, or phenyl (C₁-C₆)alkyl, wherein the cyclic portions of each are optionally substituted with 1, 2, or 3 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, hydroxyl, CF₃, or OCF₃.

In another aspect, the invention provides compounds of formula X-mm, i.e., compounds of formula X-ll, wherein R₁₇ is C₁-C₄ alkoxy, cyclohexyl, or C₁-C₄ alkyl.

In another aspect, the invention provides compounds of formula X-nn, i.e., compounds of formula X-ll, wherein R₁₇ is C₁-C₄ alkoxy.

In another aspect, the invention provides compounds of formula X-oo, i.e., compounds of formula X-ll, wherein R₁₇ is cyclohexyl, or C₁-C₄ alkyl.

In another aspect, the invention provides compounds of formula X-pp, i.e., compounds of formula X-ll, wherein R₁₇ is phenyloxy, phenyl C₁-C₄ alkyl (preferably benzyl or phenethyl, more preferably, benzyl), or phenyl.

In another aspect, the invention provides compounds of formula X-qq, i.e., compounds of formula X-ll, wherein R₁₇ is pyridyl, pyrazinyl, or pyrimidinyl.

In another aspect, the invention provides compounds of formula X-qq, i.e., compounds of formula X-ll, wherein R₁₇ is —NR₁₈R₁₉, and R₁₈ is H.

In another aspect, the invention provides compounds of formula X-rr, i.e., compounds of formula X-qq, wherein R₁₉ is H, C₁-C₆ alkyl, phenyl, naphthyl, pyridyl, pyrrolyl, piperazinyl, pyrimidinyl, furanyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, or phenyl (C₁-C₆)alkyl, wherein the cyclic portions of each are optionally substituted with 1, 2, or 3 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, hydroxyl, CF₃, or OCF₃.

In another aspect, the invention provides compounds of formula X-ss, i.e., compounds of formula X-ff, wherein R₇ is —(C₁-C₄ alkyl) —C(O) NR₃₀R₃₁, —O—(C₁-C₄ alkyl)-C(O)NR₃₀R₃₁, —C(O)NR₃₀R₃₁. In another aspect, R₇ is —(C₁-C₂ alkyl)-C(O)NR₃₀R₃₁, —O—(C₁-C₂ alkyl)-C(O)NR₃₀R₃₁, or —C(O)NR₃₀R₃₁. In still another aspect, R₇ is —(C₁-C₂ alkyl)-C(O)NR₃₀R₃₁ (where the C₁-C₂ alkyl is —CH₂—, —CH₂CH₂—, or —CH(CH₃)—.) In yet still another aspect, R₇ is —O—(C₁-C₂ alkyl)-C(O)NR₃₀R₃₁ (where the —O—(C₁-C₂ alkyl) is —O—CH₂—, —O—CH₂CH₂—, or —O—CH(CH₃)—.) In still yet another aspect, R₇ is —C(O)NR₃₀R₃₁.

In another aspect, the invention provides compounds of formula X-tt, i.e., compounds of formula X-ss, wherein R₃₀, R₃₁, and the nitrogen to which they are attached form a heterocycloalkyl ring that is pyrrolidinyl, piperidinyl, morpholinyl, dihydro 1H-indolyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, or piperazinyl, wherein the heterocyclic ring is optionally substituted with 1, 2, or 3 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, C₁-C₄ thioalkoxy, OH, NH₂, NH(C₁-C₄ alkyl), N(C₁-C₄ alkyl) (C₁-C₄ alkyl), CF₃, OCF₃, phenyl, 4-halophenyl, —(C₁-C₄ alkyl)-N(H or C₁-C₄ alkyl)-phenyl, C₁-C₄ hydroxyalkyl, phenyl C₁-C₄ alkoxy, phenyl C₁-C₄ alkyl, phenyl C₁-C₄ alkanoyl, —CH₂-pyrrolidinyl, C(O)NH₂, C(O)NH(C₁-C₆ alkyl), C(O)N(C₁-C₆ alkyl) (C₁-C₆ alkyl), C₁-C₆ alkoxycarbonyl, C₂-C₆ alkanoyl, pyrazolyl, pyrrolyl, pyridyl, furanyl, morpholinyl, or —SO₂—(C₁-C₄ alkyl).

In another aspect, the invention provides compounds of formula X-uu, i.e., compounds of formula X-tt, wherein R₃₀, R₃₁, and the nitrogen to which they are attached form a heterocycloalkyl ring that is optionally substituted with 1 or 2 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, C₁-C₄ thioalkoxy, OH, NH₂, NH (C₁-C₄ alkyl), N(C₁-C₄ alkyl) (C₁-C₄ alkyl), —CH₂-pyrrolidinyl, —C(O)NH₂, —C(O)NH(C₁-C₄ alkyl), or —C(O)N(C₁-C₄ alkyl) (C₁-C₄ alkyl), CF₃, OCF₃, phenyl, 4-halophenyl, or —(C₁-C₄ alkyl)-N(H or C₁-C₄ alkyl)-phenyl.

In another aspect, the invention provides compounds of formula X-vv, i.e., compounds of formula X-tt, wherein R₃₀, R₃₁, and the nitrogen to which they are attached form a heterocycloalkyl ring that is optionally substituted with 1 or 2 groups that are independently C(O)NH₂, C(O)NH(C₁-C₄ alkyl), C(O)N(C₁-C₄ alkyl) (C₁-C₄ alkyl), C₁-C₄ alkoxycarbonyl, C₂-C₆ alkanoyl, pyrazolyl, pyrrolyl, pyridyl, or —SO₂—(C₁-C₄ alkyl).

In another aspect, the invention provides compounds of formula X-vvl, i.e., compounds of formula X-tt, wherein R₃₀, R₃₁, and the nitrogen to which they are attached form a pyrrolidinyl ring that is optionally substituted with phenyl, methyl, ethyl, —CH₂OH, —CH₂NH-phenyl, —CH₂-pyrrolidinyl, —C(O)NH₂, —C(O)NH(C₁-C₄ alkyl), or —C(O)N(C₁-C₄ alkyl) (C₁-C₄ alkyl).

In another aspect, the invention provides compounds of formula X-vv2, i.e., compounds of formula X-tt, wherein R₃₀, R₃₁, and the nitrogen to which they are attached form dihydro 1H-indolyl.

In another aspect, the invention provides compounds of formula X-ww, i.e., compounds of formula X-ss, wherein R₃₁ is H, C₁-C₄ alkyl (in another aspect, methyl or ethyl), C₂-C₆ alkenyl (in another aspect, allyl), C₃-C₆ cycloalkyl (in another aspect, cyclopropyl, cyclohexyl, tetrahydronaphthyl, or indanyl), hydroxy C₁-C₄ alkyl (in another aspect, C₂ hydroxyalkyl), phenyl C₁-C₄ alkyl (in another aspect, benzyl, phenethyl or phenpropyl), or pyridyl C₁-C₄ alkyl (in another aspect, —CH₂-pyridyl).

In another aspect, the invention provides compounds of formula X-ww1, i.e., compounds of formula X-ww, wherein R₃₁ is H.

In another aspect, the invention provides compounds of formula X-xx, i.e., compounds of either formula X-ww or formula X-wwl, wherein R₃₀ is H or C₁-C₆ alkyl, wherein the alkyl group is optionally substituted with 1, 2, or 3 groups that are independently halogen, OH, phenyl, or alkoxy optionally substituted with OH or phenyl.

In another aspect, the invention provides compounds of formula X-yy, i.e., compounds of either formula X-ww or formula X-ww1, wherein R₃₀ is phenyl, —CH₂CH₂-phenyl, —CH(CH₃)-phenyl, —C(CH₃)₂-phenyl, benzyl, naphthyl C₁-C₆ alkyl, or phenyl C₁-C₄ alkanoyl, wherein the phenyl portions of the above are optionally substituted with 1, 2, or 3 groups that are C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, C₁-C₄ thioalkoxy, OH, NH₂, NH(C₁-C₄ alkyl), N(C₁-C₄ alkyl) (C₁-C₄ alkyl), CF₃, OCF₃, phenyl, 4-halophenyl, —(C₁-C₄ alkyl) —N(H or C₁-C₄ alkyl)-phenyl, C₁-C₄ hydroxyalkyl, phenyl C₁-C₄ alkoxy, phenyl C₁-C₄ alkyl, phenyl C₁-C₄ alkanoyl, C(O)NH₂, C(O)NH(C₁-C₄ alkyl), C(O)N(C₁-C₄ alkyl) (C₁-C₄ alkyl), C₁-C₄ alkoxycarbonyl, C₂-C₄ alkanoyl, pyrazolyl, pyrrolyl, pyridyl, furanyl, morpholinyl, or —SO₂—(C₁-C₄ alkyl).

In another aspect, the invention provides compounds of formula X-zz, i.e., compounds of formula X-yy, wherein the cyclic portions are optionally substituted with 1, 2, or 3 groups that are C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, C₁-C₄ thioalkoxy, OH, CF₃, OCF₃, phenyl, 4-halophenyl, C₁-C₄ hydroxyalkyl, or —SO₂—(C₁-C₄ alkyl).

In another aspect, the invention provides compounds of formula X-aaa, i.e., compounds of formula X-zz, wherein the phenyl portions are optionally substituted with 1 or 2 groups that are independently halogen, methyl, methoxy, CF₃ or OCF₃.

In another aspect, the invention provides compounds of formula X-aa1, i.e., compounds of either formula X-ww or formula X-ww1, wherein R₃₀ is phenyl, —CH(CH₃)-phenyl, or benzyl, wherein the phenyl portions of the above are optionally substituted with 1, 2, or 3 groups that are C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, C₁-C₄ thioalkoxy, OH, NH₂, NH (C₁-C₄ alkyl), N(C₁-C₄ alkyl) (C₁-C₄ alkyl), CF₃, OCF₃, phenyl, 4-halophenyl, —(C₁-C₄ alkyl)-N(H or C₁-C₄ alkyl)-phenyl, C₁-C₄ hydroxyalkyl, phenyl C₁-C₄ alkoxy, phenyl C₁-C₄ alkyl, phenyl C₁-C₄ alkanoyl, C(O)NH₂, C(O)NH(C₁-C₄ alkyl), C(O)N(C₁-C₄ alkyl) (C₁-C₄ alkyl), C₁-C₄ alkoxycarbonyl, C₂-C₄ alkanoyl, pyrazolyl, pyrrolyl, pyridyl, furanyl, morpholinyl, or —SO₂—(C₁-C₄ alkyl).

In another aspect, the invention provides compounds of formula X-bbb, i.e., compounds of formula X-zz, wherein the phenyl portions are substituted with 2 groups, one of which is a halogen and the other is either a halogen, a methyl or methoxy group.

In another aspect, the invention provides compounds of formula X-ccc, i.e., compounds of either formula X-ww or formula X-ww1, wherein R₃₀ is C₂-C₆ alkenyl (in one aspect C₃-C₄ alkenyl), or C₂-C₄ alkynyl (in one aspect, C₃ alkynyl.)

In another aspect, the invention provides compounds of formula X-ddd, i.e., compounds of either formula X-ww or formula X-ww1, wherein R₃₀ is C₃-C₆ cycloalkyl, or cyclohexenyl, each of which is optionally substituted with 1 or 2, groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, —CH₂OH, —O-benzyl, halo, OH, —C(O) NH₂, —C(O)NH(C₁-C₆ alkyl), or —C(O)N(C₁-C₆ alkyl) (C₁-C₆ alkyl). In another aspect, the cycloalkyl and cyclohexenyl groups are not substituted.

In another aspect, the invention provides compounds of formula X-eee, i.e., compounds of either formula X-ww or formula X-ww1, wherein R₃₀ is piperidinyl optionally substituted with C₁-C₄ alkyl, C₁-C₄ alkoxycarbonyl, or C₂-C₆ alkanoyl, tetrahydronaphthyl, tetrahydrofuranyl, pyrrolidinyl, pyrazolyl, dihydrofuranonyl, naphthyl, quinuclidinyl, 4H-pyranonyl (preferably 3-hydroxy 4H-pyranonyl), 1,4-dioxanyl, pyridyl, imidazolyl, thiazolyl, oxazolyl, or indolyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, C₁-C₄ thioalkoxy, OH, NH₂, NH(C₁-C₄ alkyl), N(C₁-C₄ alkyl) (C₁-C₄ alkyl), CF₃, OCF₃, phenyl, 4-(chloro or fluoro)phenyl, —(C₁-C₄ alkyl) —N(H or C₁-C₄ alkyl) -phenyl, C₁-C₄ hydroxyalkyl, phenyl C₁-C₄ alkoxy, phenyl C₁-C₄ alkyl, phenyl C₁-C₄ alkanoyl, C(O)NH₂, C(O)NH(C₁-C₆ alkyl), C(O)N(C₁-C₄ alkyl) (C₁-C₄ alkyl), C₁-C₄ alkoxycarbonyl, C₂-C₄ alkanoyl, pyrazolyl, pyrrolyl, pyridyl, furanyl, or —SO₂—(C₁-C₄ alkyl). In another aspect, R₃₀ is not substituted.

In another aspect, the invention provides compounds of formula X-fff, i.e., compounds of either formula X-ww or formula X-wwl, wherein R₃₀ is tetrahydronaphthyl C₁-C₄ alkyl, tetrahydrofuranyl C₁-C₄ alkyl, pyridyl C₁-C₄ alkyl, pyrazolyl C₁-C₄ alkyl, cyclohexenyl C₁-C₄ alkyl, pyrrolidinyl C₁-C₄ alkyl, pyrazolyl C₁-C₄ alkyl, quinuclidinyl C₁-C₄ alkyl, 4H-pyranonyl C₁-C₄ alkyl (preferably 3-hydroxy 4H-pyranonyl C₁-C₄ alkyl), pyrazinyl C₁-C₄ alkyl, pyrrolidinyl C₁-C₄ alkyl, furanyl C₁-C₄ alkyl, thienyl C₁-C₄ alkyl, pyrrolyl C₁-C₄ alkyl, 2,5-dihydro-1H-pyrrolyl C₁-C₄ alkyl, thiazolyl C₁-C₄ alkyl, biphenyl C₁-C₄ alkyl, benzothienyl C₁-C₄ alkyl, furanyl C₁-C₄ alkyl, isoxazolyl C₁-C₄ alkyl, or 1,4-dioxanyl C₁-C₄ alkyl, wherein the alkyl portions of the above are optionally substituted with 1 or 2 groups that are independently NH₂, NH(C₁-C₄ alkyl), N(C₁-C₄ alkyl) (C₁-C₄ alkyl), OH, C₁-C₄ thioalkoxy, CN, halogen, or C₁-C₄ alkoxy optionally substituted with OH or phenyl; and wherein the cyclic portion of R₃₀ is optionally substituted with 1, 2, or 3 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, C₁-C₄ thioalkoxy, OH, NH₂, NH (C₁-C₄ alkyl), N(C₁-C₄ alkyl) (C₃-C₄ alkyl), CF₃, OCF₃, phenyl, 4-(chloro or fluoro) phenyl, —(C₁-C₄ alkyl)-N(H or C₁-C₄ alkyl) -phenyl, C₁-C₄ hydroxyalkyl, phenyl C₁-C₄ alkoxy, phenyl C₁-C₄ alkyl, phenyl C₁-C₄ alkanoyl, C(O)NH₂, C(O)NH(C₁-C₄ alkyl), C(O)N(C₁-C₄ alkyl) (C₃-C₄ alkyl), C₁-C₄ alkoxycarbonyl, C₂-C₄ alkanoyl, pyrazolyl, pyrrolyl, pyridyl, or —SO₂—(C₃-C₄ alkyl).

In another aspect, the invention provides compounds of formula X-ggg, i.e., compounds of formula fff, wherein R₃₀ is —CH₂-tetrahydronaphthyl, —CH₂-tetrahydrofuranyl, —CH₂-pyridyl, —CH₂-pyrazolyl, —CH₂-cyclohexenyl, —CH₂-pyrrolidinyl, —CH₂-pyrazolyl, —CH₂-(4H-pyranonyl) (preferably —CH₂-(3-hydroxy 4H-pyranonyl), —CH₂-pyrazinyl, —CH₂-pyrrolidinyl, —CH₂-furanyl, —CH₂-thienyl, —CH₂-pyrrolyl, —CH₂-(2,5-dihydro-1H-pyrrolyl), —CH₂-thiazolyl,

—CH₂-benzothienyl, —CH₂-furanyl, —CH₂-isoxazolyl, or —CH₂-(1,4-dioxanyl), wherein the alkyl portions of the above are optionally substituted with OH, and wherein the cyclic portion of R₃₀ is optionally substituted with 1, or 2, or 3 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, C₁-C₄ thioalkoxy, OH, NH₂, NH (C₁-C₄ alkyl), N(C₁-C₄ alkyl) (C₁-C₄ alkyl), CF₃, OCF₃, phenyl, 4-(chloro or fluoro)phenyl, —(C₁-C₄ alkyl)-N(H or C₁-C₄ alkyl)-phenyl, C₃-C₄ hydroxyalkyl, benzyloxy, benzyl, phenyl C₁-C₄ alkanoyl, C(O)NH₂, C(O)NH(C₁-C₄ alkyl), C(O)N(C₃-C₄ alkyl) (C₁-C₄ alkyl), C₁-C₄ alkoxycarbonyl, C₂-C₄ alkanoyl, pyrazolyl, pyrrolyl, pyridyl, or —SO₂CH₃.

In another aspect, the invention provides compounds of formula X-hhh, i.e., compounds of formula ff, wherein R₇ is triazolyl, tetrazolyl, pyridyl, oxazolyl, or oxadiazolyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₄ alkoxy C₁-C₄ alkyl, pyridyl, pyrrolyl, imidazolyl, furanyl, thienyl optionally substituted with 1 or 2 methyls, halogen, C₃-C₆ cycloalkyl (in one aspect, cyclohexyl) or phenyl optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, OH, C₃-C₆ alkyl, C₁-C₄ alkoxy, CF₃, OCF₃, CN, or C₁-C₆ thioalkoxy.

In another aspect, the invention provides compounds of formula X-iii, i.e., compounds of formula hhh, wherein R₇ is oxadiazolyl, which is optionally substituted with 1 group that is independently C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy C₁-C₄ alkyl, pyridyl, pyrrolyl, imidazolyl, furanyl, thienyl optionally substituted with 1 or 2 methyls, halogen, C₃-C₆ cycloalkyl (in one aspect, cyclohexyl) or phenyl optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, OCF₃, CN, or C₁-C₄ thioalkoxy.

In another aspect, the invention provides compounds of formula X-jjj, i.e., compounds of formula iii, wherein R₇ is oxadiazolyl, which is substituted with 1 group that is C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy C₁-C₄ alkyl, or halogen.

In another aspect, the invention provides compounds of formula X-kkk, i.e., compounds of formula iii, wherein R₇ is oxadiazolyl, which is substituted with 1 group that is pyridyl, pyrrolyl, imidazolyl, furanyl, thienyl optionally substituted with 1 or 2 methyls, C₃-C₆ cycloalkyl (in one aspect, cyclohexyl) or phenyl optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, OCF₃, CN, or C₁-C₄ thioalkoxy.

In another aspect, the invention provides compounds of formula X-111, i.e., compounds of formula kkk, wherein R₇ is oxadiazolyl, which is substituted with 1 group that is pyridyl, or phenyl, wherein the phenyl is optionally substituted with 1, 2, or 3 groups that are independently halogen, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, OCF₃, CN, or C₁-C₄ thioalkoxy. In another aspect, the phenyl group is unsubstituted or mono-substituted. In still another aspect, when the phenyl group is mono-substituted, it is substituted at the 3 or 4 position.

In another aspect, the invention provides compounds of formula X-mmm, i.e., compounds of formula kkk, wherein R₇ is oxadiazolyl, which is substituted with 1 group that is pyrrolyl, imidazolyl, furanyl, thienyl optionally substituted with 1 or 2 methyls, C₃-C₆ cycloalkyl (in one aspect, cyclohexyl)

In another aspect, the invention provides compounds of formula X-nnn, i.e., compounds of formula hhh, wherein R₇ is tetrazolyl.

Definitions

The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims.

It should be noted that, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to a composition containing “a compound” includes a mixture of two or more compounds. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.

Where multiple substituents are indicated as being attached to a structure, it is to be understood that the substituents can be the same or different. Thus for example “R_(m) optionally substituted with 1, 2 or 3 R_(q) groups” indicates that R_(m) is substituted with 1, 2, or 3 R_(q) groups where the R_(q) groups can be the same or different.

APP, amyloid precursor protein, is defined as any APP polypeptide, including APP variants, mutations, and isoforms, for example, as disclosed in U.S. Pat. No. 5,766,846. A beta, amyloid beta peptide, is defined as any peptide resulting from beta-secretase mediated cleavage of APP, including peptides of 39, 40, 41, 42, and 43 amino acids, and extending from the beta-secretase cleavage site to amino acids 39, 40, 41, 42, or 43.

Pharmaceutically acceptable refers to those properties and/or substances that are acceptable to the patient from a toxicological and/or safety point of view.

A therapeutically effective amount is defined as an amount effective to reduce or lessen at least one symptom of the disease being treated or to reduce or delay onset of one or more clinical markers or symptoms of the disease.

By “alkyl” and “C₁-C₆ alkyl” in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, such as, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. It is understood that in cases where an alkyl chain of a substituent (e.g. of an alkyl, alkoxy or alkenyl group) is shorter or longer than 6 carbons, it will be so indicated in the second “C” as, for example, “C₁-C₁₀” indicates a maximum of 10 carbons.

By “alkoxy” and “C₁-C₆ alkoxy” in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, attached through at least one divalent oxygen atom, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, hexoxy, and 3-methylpentoxy.

By the term “halogen” in the present invention is meant fluorine, bromine, chlorine, and/or iodine.

“Alkenyl” and “C₂-C₆ alkenyl” means straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and from one to three double bonds and includes, for example, ethenyl, propenyl, 1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyl and the like.

“Alkynyl” and “C₂-C₆ alkynyl” means straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and one or two triple bonds and includes ethynyl, propynyl, butynyl, pentyn-2-yl and the like.

As used herein, the term “cycloalkyl” refers to saturated carbocyclic radicals having three to twelve carbon atoms. The cycloalkyl can be monocyclic, a polycyclic fused system, or a bi or polycyclic bridged system, such as adamantyl or bicyclo[2.2.1] heptyl. Cycloalkyl groups can also be fused to a phenyl group. Examples of such cycloalkyl groups include 1,2,3,4-tetrahydronaphthyl, indanyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Preferred cycloalkyl groups are cyclopentyl, cyclohexyl, and cycloheptyl. The cycloalkyl groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. For example, such cycloalkyl groups may be optionally substituted with, for example, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl, mono(C₁-C₆)alkylamino(C₁-C₆)alkyl or di(C₁-C₆)alkylamino(C₁-C₆)alkyl.

By “aryl” is meant an aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings in which at least one is aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl), which is optionally mono-, di-, or trisubstituted. Preferred aryl groups of the present invention are phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, fluorenyl, tetralinyl or 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl. The aryl groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. For example, such aryl groups may be optionally substituted with, for example, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, C₂- C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl, mono(C₁-C₆)alkylamino(C₁-C₆)alkyl or di(C₁-C₆)alkylamino(C₁-C₆)alkyl.

By “heteroaryl” is mean at least one or more aromatic ring systems of 5-, 6-, or 7-membered rings which includes fused ring systems of 9-11 atoms containing at least one and up to four heteroatoms selected from nitrogen, oxygen, or sulfur. Preferred heteroaryl groups of the present invention include pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, triazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, isothiazolyl, naphthyridinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, chromonyl, chromanonyl, pyridinyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide. The heteroaryl groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. For example, such heteroaryl groups may be optionally substituted with, for example, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynynyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, amino (C₁-C₆) alkyl, mono(C₁-C₆)alkylamino(C₁-C₆)alkyl or di(C₁-C₆)alkylamino(C₁-C₆)alkyl.

By “heterocycle”, “heterocycloalkyl” or “heterocyclyl” is meant one or more carbocyclic ring systems of 4-, 5-, 6-, or 7-membered rings which includes fused ring systems of 9-11 atoms containing at least one and up to four heteroatoms selected from nitrogen, oxygen, or sulfur. Preferred heterocycles of the present invention include morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-dioxide and homothiomorpholinyl S-oxide. The heterocycle groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. For example, such heterocycle groups may be optionally substituted with, for example, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino, mono (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl, mono(C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl or ═O.

Structures were named using Name Pro IUPAC Naming Software, version 5.09, available from Advanced Chemical Development, Inc., 90 Adelaide Street West, Toronto, Ontario, M5H 3V9, Canada or using ChemDraw v. 6.02 or ChemDraw v. 8.03, both of which are available from Cambridgesoft at 100 Cambridge Park Drive, Cambridge, Mass. 02140 (www.cambridgesoft.com).

The compounds of this invention may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates, chiral non-racemic or diastereomers. In these situations, the single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent; chromatography, using, for example a chiral HPLC column; or derivatizing the racemic mixture with a resolving reagent to generate diastereomers, separating the diastereomers via chromatography, and removing the resolving agent to generate the original compound in enantiomerically enriched form. Any of the above procedures can be repeated to increase the enantiomeric purity of a compound.

Non-toxic pharmaceutically acceptable salts include, but are not limited to salts of inorganic acids such as hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic, and nitric or salts of organic acids such as formic, citric, malic, maleic, fumaric, tartaric, succinic, acetic, lactic, methanesulfonic, p-toluenesulfonic, 2-hydroxyethylsulfonic, salicylic and stearic. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts. The invention also encompasses prodrugs of the compounds of Formula I.

The invention also encompasses the acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies, which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I.

When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, it is intended that the compounds include the cis, trans, Z- and E-configurations. Likewise, all tautomeric forms are also intended to be included.

The invention also encompasses the prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies that may be employed to prepare non-toxic pharmaceutically acceptable prodrugs of the compounds encompassed by Formula I. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable solvates, such as water, ethanol, mineral oil, vegetable oil, and dimethylsulfoxide.

The compounds of general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques and the like. In addition, there is provided a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier. One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants, and if desired other active ingredients. The pharmaceutical compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservative agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques. In some cases such coatings may be prepared by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Formulations for oral use may also be presented as lozenges.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents or suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil or a mineral oil or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compounds of general Formula I may also be administered in the form of suppositories, e.g., for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.

Compounds of general Formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.

For disorders of the eye or other external tissues, e.g., mouth and skin, the formulations are preferably applied as a topical gel, spray, ointment or cream, or as a suppository, containing the active ingredients in a total amount of, for example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w. When formulated in an ointment, the active ingredients may be employed with either paraffinic or a water-miscible ointment base.

Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. The topical formulation may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs. The compounds of this invention can also be administered by a transdermal device. Preferably topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as the membrane. The transdermal patch may include the compound in a suitable solvent system with an adhesive system, such as an acrylic emulsion, and a polyester patch. The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier, which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base, which forms the oily, dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredients are dissolved or suspended in suitable carrier, especially an aqueous solvent for the active ingredients. The anti-inflammatory active ingredients are preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% and particularly about 1.5% w/w. For therapeutic purposes, the active compounds of this combination invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.

Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient. The daily dose can be administered in one to four doses per day. In the case of skin conditions, it may be preferable to apply a topical preparation of compounds of this invention to the affected area two to four times a day.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

For administration to non-human animals, the composition may also be added to the animal feed or drinking water. It may be convenient to formulate the animal feed and drinking water compositions so that the animal takes in a therapeutically appropriate quantity of the composition along with its diet. It may also be convenient to present the composition as a premix for addition to the feed or drinking water.

The disclosures in this document of all articles and references, including patents, are incorporated herein by reference in their entirety.

The invention is illustrated further by the following examples, which are not to be construed as limiting the invention in scope or spirit to the specific procedures described in them.

The starting materials and various intermediates may be obtained from commercial sources, prepared from commercially available compounds, or prepared using known synthetic methods.

General Synthetic Procedures

The compounds of the invention can be prepared using methods well known in the art of organic synthesis. Representative procedures for preparing compounds of the invention are outlined in the following schemes.

Compounds of the invention can be prepared by various methods known to those skilled in the art. For example, the compounds of the invention, as well as all intermediates, can be synthesized by known processes using either solution or solid phase techniques, as shown below.

R₁, R₂, and n are as defined in the specification.

Using standard methods familiar to those skilled in the art, primary amine 3.0 is converted into secondary amine 4.0. Possible methods include, but are not limited to, reductive alkylations using a ketone or aldehyde, and a reducing agent, such as NaCNBH₃, NaBH₄, polystyrene bound borohydride, or H₂ and a transition metal catalyst, in a suitable solvent, such as methanol.

All of the variables are as defined in the specification.

Sulfonylation of secondary amines 4.0 with an appropriate sulfonylhalide 5.0 in a suitable solvent such as dichloromethane, chloroform, or tetrahydrofuran, in the presence of a base, such as pyridine, triethylamine, lutidine, or diisopropylethylamine, at a decreased temperature, affords compounds of formula Ib.

All of the variables are as defined in the specification. One possible method for preparing the compounds of the invention is illustrated in scheme 3. Sulfonylation of primary amines 7.0 with an appropriate sulfonylhalide 5.0 in a suitable solvent such as dichloromethane, chloroform, tetrahydrofuran, in the presence of a base such as diisopropylethylamine or triethylamine at a decreased temperature generate sulfonamides 9.0. Sulfonamides 9.0 are further functionalized by treatment with an alkyl or arylalkyl halide via nucleophilic displacement, in a solvent such as DMF, dimethylacetamide, dioxane, tetrahydrofuran, with a base such as cesium carbonate, to afford compounds of formula Ib. Alternatively, sulfonamides 9.0 can be converted into compounds of formula Ib by reacting 9.0 with a primary or secondary alcohol via a Mitsunobu reaction.

Certain compounds of this invention are prepared from other compounds listed in this invention via well-known functional group transformations. Such transformations include ester hydrolysis, amide formation, reductive alkylation, with examples of such described in the preparations. Starting materials are prepared by known methods and are described in the examples below.

Compounds included in this invention are exemplified by the following examples, which should not be construed as limiting the scope of this disclosure. Analogous structures and alternative mechanistic pathways within the scope of the invention may be apparent to those skilled in the art.

EXAMPLE 1

2-(2-Methanesulfonyl-ethyl)-pyridine (1)

To a 0.2 M solution of 2-(2-hydroxyethyl)pyridine (4.5 mmol) in methylene chloride is added triethylamine (24 mmol), followed by methanesulfonyl chloride (4.8 mmol.) The resulting mixture is stirred at room temperature overnight. The mixture is then poured into water and extracted with methylene chloride. The organic extracts are combined, washed with NaHCO₃ (sat), and then 1M aq. HCl. The acidic aqueous extracts are neutralized with NaHCO₃ (sat) and then extracted with methylene chloride. The organic extracts were combined, dried (MgSO₄), filtered, and concentrated to afford the desired product (1).

3-Methoxy-4-(2-pyridin-2-yl-ethyl)-benzaldehyde (2)

Vanillin (2.5 mmol) is added to mixture of K₂CO₃ (12.5 mmol) and 2-(2-Methanesulfonyl-ethyl)-pyridine (1) (2.5 mmol) in DMF (0.2 M), and the resulting reaction mixture is heated to 75° C. for 16 h. After cooling to approximately room temperature, water is added and the aqueous mixture is extracted 5 times with methylene chloride. The methylene chloride layers are combined and concentrated to afford a residue, which is recrystallized in diethyl ether.

3-[3-Methoxy-4-(2-pyridin-2-yl-ethoxy)-benzylamino]-azepan-2-one (3): Acetic acid (1.8 mmol) is added to 3-Methoxy-4-(2-pyridin-2-yl-ethyl)-benzaldehyde (2) (0.45 mmol) and DL-α-amino-ε-caprolactam (0.45 mmol) in a minimal amount of methanol. The resulting reaction mixture is stirred for 3 hours, and then MeOH (0.2 M) is added, followed by NaH₃BCN (0.45 mmol), which is added in three portions over 19 hours. The product (3) is obtained by purification using reverse phase HPLC.

4-Fluoro-N-[3-methoxy-4-(2-pyridin-2-yl-ethoxy)-benzyl]-N-(2-oxo-azepan-3-yl)-benzenesulfonamide (4)

4-fluorobenzenesulfonyl chloride (0.22 mmol) is added to a room temperature solution of triethylamine (0.9 mmol) and 3-[3-Methoxy-4-(2-pyridin-2-yl-ethoxy)-benzylamino]-azepan-2-one (3) (0.22 mmol) in methylene chloride (0.2 M). After stirring for 48 hours, the reaction mixture is concentrated and the resulting residue is purified by reverse phase HPLC, to afford the desired product (4).

EXAMPLE 2

5-(2-Methanesulfonyl-ethyl)-4-methyl-thiazole (5)

Methanesulfonyl chloride (5.4 mmol) was added to a methylene chloride (0.2 M) solution of 5-(2-hydroxyethyl)-4-methyl-thiazole (4.5 mmol) and triethylamine (23 mmol), and stirred at room temperature overnight. The mixture was poured into water and extracted with methylene chloride. The organic extracts were washed with NaHCO₃ (sat), and the product was extracted with 1M aq. HCl. The aqueous extracts were neutralized with NaHCO₃ (sat) and then extracted with methylene chloride. The organic extracts were dried (MgSO₄) and filtered. Solvent removal afforded product (5).

3-Methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzaldehyde (6): Vanillin (2.9 mmol) was added to mixture of K₂CO₃ (14.5 mmol) and 5-(2-Methanesulfonyl-ethyl)-4-methyl-thiazole (5) (2.9 mmol) in DMF (0.2 M), and heated to 75° C. for h. After cooling, water was added and aqueous mixture extracted 5 times with methylene chloride. The methylene chloride layers were combined and concentrated to afford the product (6).

3-{3-Methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzylamino}-azepan-2-one (7): Acetic acid (9.4 mmol) was added to 3-Methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzaldehyde (6) (2.3 mmol) and DL-α-amino-ε-caprolactam (2.3 mmol) in minimal amount of methanol and stirred for 2 h. MeOH (0.2 M) was added followed by NaH₃BCN (2.3 mmol), and the reaction was stirred for 19 h. The product (7) was obtained by purification upon reverse phase HPLC.

4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-(2-oxo-azepan-3-yl)-benzenesulfonamide (8): 4-chlorobenzenesulfonylchloride (0.26 mmol) was added to a methylene chloride (0.2 M) solution of triethylamine (1.0 mmol) and 3-{3-Methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzylamino}-azepan-2-one (7) (0.26 mmol), and stirred at room temperature for 12 h. The product (8) was obtained by purification upon reverse phase HPLC.

In the following examples, MH⁺ refers to the mass as determined by LC/MS carried out on a ThermoHypersil-Keystone BDS Hypersil C18 column (50 mm×3 mm, 5 micron particle size). MNa⁺ is used to identify the product based on it sodium adduct. Elution conditions for LC/MS are as follows: Solvents: A. Water with 0.05% TFA (v/v); B. Acetonitrile with 0.05% TFA (v/v); Flow rate: 3 mL/min

Gradient Method Time (min) % B Conc 0 5 0.25 5 2.75 95 3.5 95 3.6 5 4.0 STOP

In isolating the following examples, a Varian reverse-phase preparative HPLC, utilizing a Phenomenex Aqua C₁₈ column (60 mm×21.2 mm, 5 micron particle size) was used. Elution conditions for the HPLC are as follows: Solvents: A. Water with 0.1% TFA (v/v); B. Acetonitrile with 0.1% TFA (v/v); Flow rate: 25 mL/min.

Gradient Method Time (min) % B Conc 0 5 0.75 5 9.5 100 10.5 100 11.5 5 12.0 STOP

EXAMPLE 3

Step 1

4-chlorobenzenesulfonyl chloride (7.08 g; 30.54 mmol) was added to a 0° C. solution of D-α-amino-ε-caprolactam hydrochloride (5.0 g; 30.49 mmol) and triethylamine (25 ml; 244 mmol) in CH₂Cl₂ and was allowed to stir for 4 h at 0° C. An aqueous workup was performed, partitioning CH₂Cl₂ and water, followed by CH₂Cl₂ and 3N HCl. The organic layer was then dried with MgSO₄, filtered and concentrated. The sample was then dissolved in hot methanol (100 ml), followed by the addition of water (20 ml) and allowed to crystallize in a refrigerator over 48 h. The solution was then filtered and dried, isolating the desired product (5.42 g).

Step 2

The newly formed sulfonamide from Step 1 (60 mg, 0.2 mmol) was dissolved in DMF (1 ml) and added to a mixture of 4-bromo-2-methyl-2-butene (30 mg; 0.2 mmol) and cesium carbonate (130 mg; 0.4 mmol). The solution was sonicated and stirred for 39 h at 50° C. The crude reaction mixture was then placed on a Varian reverse-phase preparative HPLC to isolate the desired product.

EXAMPLE 4 Synthesis of D-Boc-α-amino-ε-caprolactam

In a 1L round bottom flask under a nitrogen atmosphere is placed 20 g (80 mmol) of N-α-Boc-D-lysine with 300 mL of DMF and a magnetic stir bar. 36 g of BOP is added to the room temperature slurry. The reaction is stirred for 15 minutes until clear. Then 36 g of NaHCO₃ and 100 mL of DMF are added. After 20 hours, the reaction mixture is concentrated under vacuum. The concentrated mixture is diluted with water and aqueous NaHCO₃ solution (1:1) and extracted three times with ethyl acetate. The combined organic extracts are washed with water, saturated aqueous NaHCO_(j) solution, saturated aqueous NaCl solution, dried (Na₂SO₄), filtered and concentrated to afford a residue. The residue is triturated with ether (20 mL) and filtered. Washing the precipitate with hexanes led to another crop in the filtrate. A final crop is obtained by concentrating of the second filtrate and treatment with hexanes. Combining all crops affords the desired cyclized product. MS: 229 (M+H).

Procedure for Synthesis of D-α-amino-ε-caprolactam HCl

The D-Boc-α-amino-ε-caprolactam (12 g, 52 mmol) is mixed with 130 mL of dioxane to form a cloudy solution. 30 mL of 4N HCl in dioxane is added and gas evolution is noted. After 2 hours, HPLC-MS shows incomplete reaction. Methanol (20 mL) and an additional 20 mL of 4N HCl in dioxane solution are added and stirring continued overnight. The resulting solid was filtered and dried in a vacuum oven to yield 8.85 g of the desired product. Chiral HPLC analysis showed no racemization. MS: 129 (M+H).

EXAMPLE 5

Step 1 D-Z-α-amino-ε-caprolactam.

A mixture of 5.0 grams of N-α-Z-D-lysine, 4.4 grams of HOBt, 5.5 mL of N-methylmorpholine, 200 mL of dichloromethane, and 200 mL of dimethylformamide are treated with 3.8 grams of EDC. After 18 hours the mixture is partitioned between ethyl acetate and distilled water. (The two phase mixture was filtered to remove some insoluble material prior to separating the phases.) The aqueous phase is washed with ethyl acetate, and the combined organic extracts are washed with aqueous potassium carbonate, aqueous sodium bisulfate, and finally with brine. The solution is dried over magnesium sulfate, filtered, and concentrated to afford 3.2 grams of a white solid, having m/z=285.1

D-α-amino-ε-caprolactam. All of the product from Step 1 is dissolved in 65 mL of methanol and treated with 100 mg of 10% palladium on carbon. The mixture is agitated for 36 hours under 30 psi of hydrogen, and then filtered. Mass spectral analysis shows m/z=129.

D-α-Amino-δ-valerlactam and D-α-amino-γ-butyrlactam were made by the same procedure from N-α-Z-D-ornithine and N-α-Z-D-diaminobutyric acid respectively.

The following compounds are prepared essentially according to the methods and procedures described above. The mass spectra data in the following tables is experimentally derived and not calculated.

Ex. No. Name M + H⁺ M + Na⁺ 1 4-Chloro-N-(4-hydroxy-3-methoxy- 439.1 benzyl)-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 2

475.1 4-Chloro-N-(3,4-dimethoxy-benzyl)-N- (2-oxo-azepan-3-yl)-benzenesulfonamide 3 4-Chloro-benzenesulfonic acid 4-{[(4- 613.8 chloro-benzenesulfonyl)-(2-oxo-azepan-3- yl)-amino]-methyl}-2-methoxy-phenyl ester 4 4-chloro-N-(4-chlorobenzyl)-N-[(3R)-2- 427.0 oxoazepan-3-yl]benzenesulfonamide 5 4-Butyl-N-(3,4-dimethoxy-benzyl)-N-(2- 497.2 oxo-azepan-3-yl)-benzenesulfonamide 6 N-(3,4-Dimethoxy-benzyl)-4-methoxy-N- 471.1 (2-oxo-azepan-3-yl)-benzenesulfonamide 7 7-Chloro-benzo[1,2,5]oxadiazole-4- 517.0 sulfonic acid (3,4-dimethoxy-benzyl)-(2- oxo-azepan-3-yl)-amide 8 4-Chloro-benzene-1,3-disulfonic acid 554.1 3-amide 1-[(3,4-dimethoxy-benzyl)-(2-oxo- azepan-3-yl)-amide] 9 4-Cyano-N-(3,4-dimethoxy-benzyl)-N-(2- 466.1 oxo-azepan-3-yl)-benzenesulfonamide 10 4-Bromo-N-(3,4-dimethoxy-benzyl)-N-(2- 519.0 oxo-azepan-3-yl)-benzenesulfonamide 11 N-(3,4-Dimethoxy-benzyl)-N-(2-oxo- 533.2 azepan-3-yl)-4-phenoxy-benzenesulfonamide 12 1-Oxa-2,3-diaza- 533.2 cyclopenta[a]naphthalene-5-sulfonic acid (3,4-dimethoxy-benzyl)-(2-oxo-azepan-3- yl)-amide 13 N-(3,4-Dimethoxy-benzyl)-3-methyl-N- 455.1 (2-oxo-azepan-3-yl)-benzenesulfonamide 14 4-tert-Butyl-N-(3,4-dimethoxy-benzyl)- 497.1 N-(2-oxo-azepan-3-yl)-benzenesulfonamide 15 N-(3,4-Dimethoxy-benzyl)-4-iodo-N-(2- 567.1 oxo-azepan-3-yl)-benzenesulfonamide 16 N-(3,4-Dimethoxy-benzyl)-4-isocyanato- 460.1 N-(2-oxo-azepan-3-yl)-benzenesulfonamide 17 3-Bromo-N-(3,4-dimethoxy-benzyl)-N-(2- 520.0 oxo-azepan-3-yl)-benzenesulfonamide 18 Naphthalene-2-sulfonic acid (3,4- 491.1 dimethoxy-benzyl)-(2-oxo-azepan-3-yl)- amide 19 3-Chloro-N-(3,4-dimethoxy-benzyl)-4- 493.0 fluoro-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 20 N-(3,4-Dimethoxy-benzyl)-3-fluoro-4- 473.0 methyl-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 21 3,4-Dichloro-N-(3,4-dimethoxy-benzyl)- 509.0 N-(2-oxo-azepan-3-yl)-benzenesulfonamide 22 3-Chloro-N-(3,4-dimethoxy-benzyl)-N- 475.1 (2-oxo-azepan-3-yl)-benzenesulfonamide 23 N-(3,4-Dimethoxy-benzyl)-N-(2-oxo- 441.1 azepan-3-yl)-benzenesulfonamide 24 3,5-Dichloro-N-(3,4-dimethoxy-benzyl)- 510.1 N-(2-oxo-azepan-3-yl)-benzenesulfonamide 25 N-(3,4-Dimethoxy-benzyl)-3,4- 501.2 dimethoxy-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 26 N-(3,4-Dimethoxy-benzyl)-4-methyl-N- 455.1 (2-oxo-azepan-3-yl)-benzenesulfonamide 27 N-(3,4-Dimethoxy-benzyl)-4- 519.2 methanesulfonyl-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 28 3-{4-[(3,4-Dimethoxy-benzyl)-(2-oxo- 527.1 azepan-3-yl)-sulfamoyl]-phenyl}-propionic acid methyl ester 29 N-{4-[(3,4-Dimethoxy-benzyl)-(2-oxo- 498.1 azepan-3-yl)-sulfamoyl]-phenyl}-acetamide 30 3-Chloro-N-(3,4-dimethoxy-benzyl)-4- 489.0 methyl-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 31 N-(3,4-Dimethoxy-benzyl)-N-(2-oxo- 525.1 azepan-3-yl)-4-trifluoromethoxy- benzenesulfonamide 32 4-Acetyl-N-(3,4-dimethoxy-benzyl)-N- 483.1 (2-oxo-azepan-3-yl)-benzenesulfonamide 33 N-{2-Chloro-4-[(3,4-dimethoxy-benzyl)- 532.1 (2-oxo-azepan-3-yl)-sulfamoyl]-phenyl}- acetamide 34 N-(3,4-Dimethoxy-benzyl)-N-(2-oxo- 509.1 azepan-3-yl)-3-trifluoromethyl- benzenesulfonamide 35 2-(2,2,2-Trifluoro-acetyl)-1,2,3,4- 592.2 tetrahydro-isoquinoline-7-sulfonic acid (3,4-dimethoxy-benzyl)-(2-oxo-azepan-3- yl)amide 36 3-Cyano-N-(3,4-dimethoxy-benzyl)-N-(2- 466.1 oxo-azepan-3-yl)-benzenesulfonamide 37 N-(3,4-Dimethoxy-benzyl)-4-fluoro-N- 459.1 (2-oxo-azepan-3-yl)-benzenesulfonamide 38 N-(3,4-Dimethoxy-benzyl)-3,4-difluoro- 477.0 N-(2-oxo-azepan-3-yl)-benzenesulfonamide 39 N-(3,4-Dimethoxy-benzyl)-4-(1,1- 511.2 dimethyl-propyl)-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 40 N-(3,4-Dimethoxy-benzyl)-4-isopropoxy- 499.1 N-(2-oxo-azepan-3-yl)-benzenesulfonamide 41 N-(3,4-Dimethoxy-benzyl)-N-(2-oxo- 483.2 azepan-3-yl)-4-propyl-benzenesulfonamide 42 N-(3,4-Dimethoxy-benzyl)-4-oxazol-5- 486.2 yl-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 43 N-(3,4-Dimethoxy-benzyl)-N-(2-oxo- 507.1 azepan-3-yl)-4-pyrazol-1-yl- benzenesulfonamide 44 4-Bromo-N-(3,4-dimethoxy-benzyl)-3- 538.1 fluoro-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 45 4-Chloro-N-(3,4-dimethoxy-benzyl)-2,5- 511.0 difluoro-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 46 N-(3,4-Dimethoxy-benzyl)-3,5-difluoro- 477.1 N-(2-oxo-azepan-3-yl)-benzenesulfonamide 47 Biphenyl-4-sulfonic acid (3,4- 517.1 dimethoxy-benzyl)-(2-oxo-azepan-3-yl)- amide 48 N-(3,4-Dimethoxy-benzyl)-2,3,4- 495.1 trifluoro-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 49 N-(3,4-Dimethoxy-benzyl)-2,4,5- 495.1 trifluoro-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 50 N-(3,4-Dimethoxy-benzyl)-2,3,4,5,6- 531.0 pentafluoro-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 51 N-(3,4-Dimethoxy-benzyl)-4-isopropyl- 483.2 N-(2-oxo-azepan-3-yl)-benzenesulfonamide 52 4-Chloro-N-cyclopropylmethyl-N-(2-oxo- 380 azepan-3-yl)-benzenesulfonamide 53 N-But-2-enyl-4-chloro-N-(2-oxo-azepan- 358 3-yl)-benzenesulfonamide 54 4-Chloro-N-(2-oxo-azepan-3-yl)-N- 374.1 pentyl-benzenesulfonamide 55 4-Chloro-N-(2-ethyl-butyl)-N-(2-oxo- 388.1 azepan-3-yl)-benzenesulfonamide 56 4-Chloro-N-hexyl-N-(2-oxo-azepan-3- 388.1 yl)-benzenesulfonamide 57 4-Chloro-N-(3-methylsulfanyl-propyl)- 392 N-(2-oxo-azepan-3-yl)-benzenesulfonamide 58 4-Chloro-N-heptyl-N-(2-oxo-azepan-3- 402.1 yl)-benzenesulfonamide 59 4-Chloro-N-(2-oxo-azepan-3-yl)-N-(3- 442 phenyl-allyl)-benzenesulfonamide 60 4-Chloro-N-nonyl-N-(2-oxo-azepan-3- 430.2 yl)-benzenesulfonamide 61 6-[(4-Chloro-benzenesulfonyl)-(2-oxo- 432.2 azepan-3-yl)-amino]-hexanoic acid methyl ester 62 4-Chloro-N-(2-methyl-3-phenyl-allyl)- 457 N-(2-oxo-azepan-3-yl)-benzenesulfonamide 63 N-(2-Benzyloxy-ethyl)-4-chloro-N-(2- 438.1 oxo-azepan-3-yl)-benzenesulfonamide 64 N-(2-Bromo-3-phenyl-allyl)-4-chloro-N- 498.9 (2-oxo-azepan-3-yl)-benzenesulfonamide 65 4-[(4-Chloro-benzenesulfonyl)-(2-oxo- 430.1 azepan-3-yl)-amino]-3-methyl-but-2-enoic acid ethyl ester 66 4-Chloro-N-(2-ethyl-allyl)-N-(2-oxo- 372 azepan-3-yl)-benzenesulfonamide 67 4-Chloro-N-(2,2-dimethyl-propyl)-N-(2- 374.1 oxo-azepan-3-yl)-benzenesulfonamide 68 4-Chloro-N-isobutyl-N-(2-oxo-azepan-3- 359.8 yl)-benzenesulfonamide 69 methyl (2-{[(4- 427.1 chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- yl]amino}ethyl)carbamate 70 N-Butyl-4-chloro-N-(2-oxo-azepan-3- 360 yl)-benzenesulfonamide 71 4-Chloro-N-(3-methyl-but-2-enyl)-N-(2- 394.1 oxo-azepan-3-yl)-benzenesulfonamide 72 4-Chloro-N-(3-methyl-butyl)-N-(2-oxo- 374.1 azepan-3-yl)-benzenesulfonamide 73 4-Chloro-N-(2-oxo-azepan-3-yl)-N- 408 phenethyl-benzenesulfonamide 74 N-(1,3-benzodioxol-5-ylmethyl)-4- 437.0 chloro-N-[(3R)-2-oxoazepan-3- yl]benzenesulfonamide 75 4-chloro-N-(3-fluoro-4-methoxybenzyl)- 463.1 N-[(3R)-2-oxoazepan-3- yl]benzenesulfonamide 76 4-chloro-N-(3,4-dimethylbenzyl)-N- 421.0 [(3R)-2-oxoazepan-3-yl]benzenesulfonamide 77 4-chloro-N-(2,3-dihydro-1,4- 473.0 benzodioxin-6-ylmethyl)-N-[(3R)-2- oxoazepan-3-yl]benzenesulfonamide 78 4-chloro-N-(4-methoxybenzyl)-N-[(3R)- 445.1 2-oxoazepan-3-yl]benzenesulfonamide 79 4-Chloro-N-naphthalen-2-ylmethyl-N-(2- 444 oxo-azepan-3-yl)-benzenesulfonamide 80 4-Chloro-N-(3-iodo-benzyl)-N-(2-oxo- 520.1 azepan-3-yl)-benzenesulfonamide 81 4-chloro-N-(cyclohexylmethyl)-N-[(3R)- 399.8 2-oxoazepan-3-yl]benzenesulfonamide 82 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N- 451.8 (4-phenoxybutyl)benzenesulfonamide 83 N-[4-(benzyloxy)butyl]-4-chloro-N- 465.8 [(3R)-2-oxoazepan-3-yl]benzenesulfonamide 84 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N- 421.1 (3-phenylpropyl)benzenesulfonamide 85 4-chloro-N-[(2E)-2-methyl-3- 455.1 phenylprop-2-en-1-yl]-N-[(3R)-2-oxoazepan- 3-yl]benzenesulfonamide 86 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N- 441.1 [(2E)-3-phenylprop-2-en-1- yl]benzenesulfonamide 87 4-chloro-N-[(3R)-2-oxoazepan-3- 303.0 yl]benzenesulfonamide 88

421.8 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N- (3-phenylpropyl)benzenesulfonamide 89 N-[3-(benzyloxy)propyl]-4-chloro-N- 451.9 [(3R)-2-oxoazepan-3-yl]benzenesulfonamide 90 N-sec-Butyl-4-chloro-N-(2-oxo-azepan- 360 3-yl)-benzenesulfonamide 91 tert-butyl ((1S)-1-benzyl-2-{[(4- 559.1 chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- yl]amino}ethyl)carbamate 92 tert-butyl ((1S)-2-{[(4- 483.2 chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- yl]amino}-1-methylethyl)carbamate 93 {2-[(4-Chloro-benzenesulfonyl)-(2-oxo- 469.1 azepan-3-yl)-amino]-ethyl}-carbamic acid tert-butyl ester 94 4-Chloro-N-(2,2-diphenyl-ethyl)-N-(2- 506 oxo-azepan-3-yl)-benzenesulfonamide 95 N-[3-(4-tert-Butyl-phenyl)-2-methyl- 491.9 propyl]-4-chloro-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 96 4-Chloro-N-(2-methyl-4-phenyl-pentyl)- 463.8 N-(2-oxo-azepan-3-yl)-benzenesulfonamide 97 4-Chloro-N-[3-(4-methoxy-phenyl)- 472 allyl]-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 98 4-chloro-N-(3-methylbut-2-en-1-yl)-N- 393.8 [(3R)-2-oxoazepan-3-yl]benzenesulfonamide 99 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N- 341.8 prop-2-yn-1-ylbenzenesulfonamide 100 4-chloro-N-isobutyl-N-[(3R)-2- 359.8 oxoazepan-3-yl]benzenesulfonamide 101 4-chloro-N-[2-(1,3-dioxo-2,3-dihydro- 476.9 1H-inden-2-yl)ethyl]-N-[(3R)-2-oxoazepan- 3-yl]benzenesulfonamide 102 4-chloro-N-(8-hydroxyoctyl)-N-[(3R)-2- 431.9 oxoazepan-3-yl]benzenesulfonamide 103 4-chloro-N-[3-(1,3-dioxo-2,3-dihydro- 490.9 1H-inden-2-yl)propyl]-N-[(3R)-2-oxoazepan- 3-yl]benzenesulfonamide 104 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N- 401.8 (tetrahydro-2H-pyran-2- ylmethyl)benzenesulfonamide 105 4-chloro-N-decyl-N-[(3R)-2-oxoazepan- 443.9 3-yl]benzenesulfonamide 106 4-chloro-N-(1,3-dioxolan-2-ylmethyl)- 389.6 N-[(3R)-2-oxoazepan-3- yl]benzenesulfonamide 107 N2-[(4-chlorophenyl)sulfonyl]-N2- 360.7 [(3R)-2-oxoazepan-3-yl]glycinamide 108 4-chloro-N-[4-(1,3-dioxo-2,3-dihydro- 504.9 1H-inden-2-yl)butyl]-N-[(3R)-2-oxoazepan- 3-yl]benzenesulfonamide 109 4-chloro-N-(6-methylheptyl)-N-[(3R)-2- 415.9 oxoazepan-3-yl]benzenesulfonamide 110 N-butyl-4-chloro-N-[(3R)-2-oxoazepan- 359.8 3-yl]benzenesulfonamide 111 4-chloro-N-[3-(4- 451.9 methoxyphenyl)propyl]-N-[(3R)-2-oxoazepan- 3-yl]benzenesulfonamide 112 ethyl 6-{[(4- 445.8 chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- yl]amino}hexanoate 113 4-Chloro-N-{3-methoxy-4-[2-(4-methyl- 565.6 thiazol-5-yl)-ethoxy]-benzyl}-N-(2-oxo- azepan-3-yl)-benzene sulfonamide 114 4-Fluoro-N-[3-methoxy-4-(2-pyridin-2- 528.6 yl-ethoxy)-benzyl]-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 115 N-[3-Methoxy-4-(2-pyridin-2-yl- 524.6 ethoxy)-benzyl]-4-methyl-N-(2-oxo-azepan- 3-yl)-benzenesulfonamide 116 3,4-Difluoro-N-{3-methoxy-4-[2-(4- 566.6 methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-(2- oxo-azepan-3-yl)-benzenesulfonamide 117 N-{3-Methoxy-4-[2-(4-methyl-thiazol-5- 598.6 yl)-ethoxy]-benzyl}-N-(2-oxo-azepan-3-yl)- 4-trifluoromethyl-benzenesulfonamide 118 3-Fluoro-N-{3-methoxy-4-[2-(4-methyl- 548.6 thiazol-5-yl)-ethoxy]-benzyl}-N-(2-oxo- azepan-3-yl)-benzenesulfonamide 119 4-Fluoro-N-{3-methoxy-4-[2-(4-methyl- 548.5 thiazol-5-yl)-ethoxy]-benzyl}-N-(2-oxo- azepan-3-yl)-benzenesulfonamide 120 4-chloro-N-{3-methoxy-4-[2-(4-methyl- 565.6 1,3-thiazol-5-yl)ethoxy]benzyl}-N-[(3R)-2- oxoazepan-3-yl]benzenesulfonamide 121 N-Benzyl-4-chloro-N-(2-oxo-azepan-3- 415.2 yl)-benzenesulfonamide 122 4-Chloro-N-(3,4-dimethoxy-benzyl)-N- 475.1 (2-oxo-azepan-3-yl)-benzenesulfonamide 123 4-chloro-N-[(3R)-2-oxopyrrolidin-3- 393 yl]-N-(3-phenylpropyl)benzenesulfonamide 124 4-chloro-N-[(2E)-2-methyl-3- 428 phenylprop-2-en-1-yl]-N-[(3R)-2- oxopyrrolidin-3-yl]benzenesulfonamide 125 4-chloro-N-dodecyl-N-[(3R)-2- 471.9 oxoazepan-3-yl]benzenesulfonamide 126 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N- 407.8 (2-phenylethyl)benzenesulfonamide 127 ethyl 5-{[(4- 431.8 chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- yl]amino}pentanoate 128 4-chloro-N-(4-methylpentyl)-N-[(3R)-2- 387.8 oxoazepan-3-yl]benzenesulfonamide 129 4-chloro-N-(2-methoxyethyl)-N-[(3R)-2- 361.8 oxoazepan-3-yl]benzenesulfonamide 130 ethyl 4-{[(4- 417.8 chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- yl]amino}butanoate 131 4-chloro-N-(6,7-dihydroxy-3,7- 475.6 dimethyloctyl)-N-[(3R)-2-oxoazepan-3- yl]benzenesulfonamide 132 4-chloro-N-((S)-3,7-dimethyloct-6- 441.8 enyl)-N-((R)-2-oxoazepan-3- yl)benzenesulfonamide 133 N-but-3-en-1-yl-4-chloro-N-[(3R)-2- 357.7 oxoazepan-3-yl]benzenesulfonamide 134 (R)-3-(4-chloro-N-(2-oxoazepan-3- 375.8 yl)phenylsulfonamido)propanoic acid 135 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N- 530.1 [(2E,6E)-3,7,11-trimethyldodeca-2,6,10- trien-1-yl]benzenesulfonamide 136 N-benzyl-4-chloro-N-[(3R)-2-oxoazepan- 415.2 3-yl]benzenesulfonamide 137

475.1 4-chloro-N-(3,4-dimethoxybenzyl)-N- [(3R)-2-oxoazepan-3-yl]benzenesulfonamide 138 4-Chloro-N-(2-oxo-azepan-3-yl)-N-(3- 422.2 phenyl-propyl)-benzenesulfonamide 139 4-chloro-N-[(3R)-2-oxopiperidin-3-yl]- 428 N-(3-phenylpropyl)benzenesulfonamide 140 4-chloro-N-[(2E)-2-methyl-3- 416 phenylprop-2-en-1-yl]-N-[(3R)-2- oxopiperidin-3-yl]benzenesulfonamide 141 4-chloro-N-(3,4-dimethoxybenzyl)-N- 428 [(3R)-2-oxopiperidin-3- yl]benzenesulfonamide 142 N-(4-bromobenzyl)-4-chloro-N-[(3R)-2- 432 oxopiperidin-3-yl]benzenesulfonamide 143 4-chloro-N-[(3R)-2-oxopiperidin-3-yl]- 462 N-[(2E)-3-phenylprop-2-en-1- yl]benzenesulfonamide 144 4-chloro-N-(4-methoxybenzyl)-N-[(3R)- 459 2-oxopiperidin-3-yl]benzenesulfonamide 145 4-chloro-N-(3-fluoro-4-methoxybenzyl)- 408 N-[(3R)-2-oxopiperidin-3- yl]benzenesulfonamide 146 4-chloro-N-(2,4-difluorobenzyl)-N- 442 [(3R)-2-oxopiperidin-3- yl]benzenesulfonamide 147 4-chloro-N-(3-fluoro-4-methoxybenzyl)- 436 N-[(3R)-2-oxopyrrolidin-3- yl]benzenesulfonamide 148 4-chloro-N-(2,4-difluorobenzyl)-N- 401 [(3R)-2-oxopyrrolidin-3- yl]benzenesulfonamide 149 4-chloro-N-[(3R)-2-oxopyrrolidin-3- 414 yl]-N-[(2E)-3-phenylprop-2-en-1- yl]benzenesulfonamide 150 4-chloro-N-(4-methoxybenzyl)-N-[(3R)- 418 2-oxopyrrolidin-3-yl]benzenesulfonamide 151 4-chloro-N-(3,4-dimethoxybenzyl)-N- 448 [(3R)-2-oxopyrrolidin-3- yl]benzenesulfonamide 152 N-(4-bromobenzyl)-4-chloro-N-[(3R)-2- 444 oxopyrrolidin-3-yl]benzenesulfonamide 153 4-Chloro-N-(3,4-dichloro-benzyl)-N-(2- 462.8 oxo-azepan-3-yl)-benzenesulfonamide 154 4-Chloro-N-(6-methoxy-naphthalen-2- 496.1 ylmethyl)-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 155 4-Chloro-N-(2-methoxy-benzyl)-N-(2- 423.7 oxo-azepan-3-yl)-benzenesulfonamide 156 4-Chloro-N-(3-methoxy-benzyl)-N-(2- 423.8 oxo-azepan-3-yl)-benzenesulfonamide 157 4-Chloro-N-(4-methoxy-benzyl)-N-(2- 423.5 oxo-azepan-3-yl)-benzenesulfonamide 158 4-Chloro-N-(2-oxo-azepan-3-yl)-N-(3- 461.8 trifluoromethyl-benzyl)-benzenesulfonamide 159 4-Chloro-N-(4-isopropoxy-benzyl)-N-(2- 451.3 oxo-azepan-3-yl)-benzenesulfonamide 160 N-(5-Bromo-thiophen-2-ylmethyl)-4- 478.4 chloro-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 161 4-Chloro-N-(2-oxo-azepan-3-yl)-N- 395 pyridin-3-ylmethyl-benzenesulfonamide 162 4-Chloro-N-(2-oxo-azepan-3-yl)-N- 394.8 pyridin-2-ylmethyl-benzenesulfonamide 163 4-Chloro-N-(2-oxo-azepan-3-yl)-N-(4- 461.8 trifluoromethyl-benzyl)-benzenesulfonamide 164 4-Chloro-N-(5,7-dimethyl-4-oxo-4H- 490.2 chromen-3-ylmethyl)-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 165 4-Chloro-N-(4-chloro-6-fluoro-2H- 521.9 chromen-3-ylmethyl)-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 166 4-Chloro-N-[5-(2,4-difluoro-phenyl)- 516.9 furan-2-ylmethyl]-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 167 4-Chloro-N-(5-chloro-1,3-dimethyl-1H- 446.7 pyrazol-4-ylmethyl)-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 168 4-Chloro-N-[5-(2-methyl-5- 569.8 trifluoromethyl-2H-pyrazol-3-yl)-thiophen- 2-ylmethyl]-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 169 N-(3-Benzyloxy-benzyl)-4-chloro-N-(2- 499.8 oxo-azepan-3-yl)-benzenesulfonamide 170 4-Chloro-N-(2-oxo-azepan-3-yl)-N-(3- 485.8 phenoxy-benzyl)-benzenesulfonamide 171 4-Chloro-N-(2-oxo-azepan-3-yl)-N-(4- 508.1 phenoxy-benzyl)-benzenesulfonamide 172 4-{[(4-Chloro-benzenesulfonyl)-(2-oxo- 451.8 azepan-3-yl)-amino]-methyl}-benzoic acid methyl ester 173 N-(4-Bromo-benzyl)-4-chloro-N-(2-oxo- 472.7 azepan-3-yl)-benzenesulfonamide 174 4-Chloro-N-(3,5-dichloro-benzyl)-N-(2- 463 oxo-azepan-3-yl)-benzenesulfonamide 175 N-[4-(4-tert-Butyl-thiazol-2-yl)- 532.7 benzyl]-4-chloro-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 176 4-Chloro-N-(1-methyl-1H-pyrrol-2- 419 ylmethyl)-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 177 4-Chloro-N-(2-oxo-azepan-3-yl)-N-(2- 462.1 trifluoromethyl-benzyl)-benzenesulfonamide 178 4-Chloro-N-(2,3-dihydro- 474 benzo[1,4]dioxin-6-ylmethyl)-N-(2-oxo- azepan-3-yl)-benzenesulfonamide 179 4-Chloro-N-(2-methoxy-naphthalen-1- 496 ylmethyl)-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 180 4-Chloro-N-(4-isobutyl-benzyl)-N-(2- 449.7 oxo-azepan-3-yl)-benzenesulfonamide 181 4-Chloro-N-(2,4-dimethoxy-benzyl)-N- 476.2 (2-oxo-azepan-3-yl)-benzenesulfonamide 182 N-(4-{[(4-Chloro-benzenesulfonyl)-(2- 472.7 oxo-azepan-3-yl)-amino]-methyl}-phenyl)- acetamide 183 4-Chloro-N-(3-chloro-4-methoxy- 480 benzyl)-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 184 N-{4-[Bis-(2-chloro-ethyl)-amino]- 534.1 benzyl}-4-chloro-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 185 3-{[(4-Chloro-benzenesulfonyl)-(2-oxo- 451.7 azepan-3-yl)-amino]-methyl}-benzoic acid methyl ester 186 4-Chloro-N-(2-morpholin-4-yl-benzyl)- 478.9 N-(2-oxo-azepan-3-yl)-benzenesulfonamide 187 4-Chloro-N-(4,6-dichloro-2H-chromen-3- 538.9 ylmethyl)-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 188 4-Chloro-N-(2-oxo-azepan-3-yl)-N- 399.6 thiophen-2-ylmethyl-benzenesulfonamide 189 4-Chloro-N-(2,6-dichloro-benzyl)-N-(2- 463.7 oxo-azepan-3-yl)-benzenesulfonamide 190 4-Chloro-N-(2-oxo-azepan-3-yl)-N- 399.7 thiophen-3-ylmethyl-benzenesulfonamide 191 N-(3-Bromo-4-fluoro-benzyl)-4-chloro- 490.8 N-(2-oxo-azepan-3-yl)-benzenesulfonamide 192 N-(5-Bromo-2-fluoro-benzyl)-4-chloro- 490.7 N-(2-oxo-azepan-3-yl)-benzenesulfonamide 193 4-Chloro-N-(2-oxo-azepan-3-yl)-N- 401 thiazol-2-ylmethyl-benzenesulfonamide 194 4-Chloro-N-(2′-methyl-biphenyl-4- 483.8 ylmethyl)-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 195 4-Chloro-N-(4-iodo-benzyl)-N-(2-oxo- 519.7 azepan-3-yl)-benzenesulfonamide 196 N-(3-Bromo-benzyl)-4-chloro-N-(2-oxo- 472.7 azepan-3-yl)-benzenesulfonamide 197 4-Chloro-N-(2,6-dimethoxy-benzyl)-N- 453.5 (2-oxo-azepan-3-yl)-benzenesulfonamide 198 4-Chloro-N-(2,3-dichloro-benzyl)-N-(2- 463.1 oxo-azepan-3-yl)-benzenesulfonamide 199 N-Biphenyl-4-ylmethyl-4-chloro-N-(2- 470.5 oxo-azepan-3-yl)-benzenesulfonamide 200 N-(4-tert-Butyl-benzyl)-4-chloro-N-(2- 449.7 oxo-azepan-3-yl)-benzenesulfonamide 201 N-(4-Benzyloxy-benzyl)-4-chloro-N-(2- 522.3 oxo-azepan-3-yl)-benzenesulfonamide 202 4-Chloro-N-(2-oxo-azepan-3-yl)-N- 402 [1,2,3]thiadiazol-4-ylmethyl- benzenesulfonamide 203 4-Chloro-N-(1-methyl-1H-indol-3- 469 ylmethyl)-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 204 N-(1-Benzyl-1H-indol-3-ylmethyl)-4- 544.9 chloro-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 205 4-Chloro-N-(2-methyl-benzyl)-N-(2-oxo- 407.8 azepan-3-yl)-benzenesulfonamide 206 N-(1-Benzenesulfonyl-1H-pyrrol-2- 545.1 ylmethyl)-4-chloro-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 207 4-Chloro-N-(2-oxo-azepan-3-yl)-N-(1- 460.8 phenyl-1H-[1,2,3]triazol-4-ylmethyl)- benzenesulfonamide 208 4-Chloro-N-(5-ethyl-furan-2-ylmethyl)- 433.9 N-(2-oxo-azepan-3-yl)-benzenesulfonamide 209 4-Chloro-N-(2,5-dimethyl-2H-pyrazol-3- 411.8 ylmethyl)-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 210 4-Chloro-N-(4,5-dimethyl-furan-2- 433.8 ylmethyl)-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 211 4-Chloro-N-(5-cyano-6-methylsulfanyl- 465.8 pyridin-2-ylmethyl)-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 212 4-Chloro-N-(4-methyl-benzyl)-N-(2-oxo- 407.9 azepan-3-yl)-benzenesulfonamide 213 5-{[(4-Chloro-benzenesulfonyl)-(2-oxo- 475.9 azepan-3-yl)-amino]-methyl}-1-methyl-1H- pyrrole-2-carboxylic acid methyl ester 214 N-(2-Bromo-benzyl)-4-chloro-N-(2-oxo- 472.8 azepan-3-yl)-benzenesulfonamide 215 4-Chloro-N-(3-methyl-benzo[b]thiophen- 463.3 2-ylmethyl)-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 216 4-Chloro-N-(3-methyl-benzyl)-N-(2-oxo- 407.8 azepan-3-yl)-benzenesulfonamide 217 4-chloro-N-(2,4-difluorobenzyl)-N- 429.8 [(3R)-2-oxoazepan-3-yl]benzenesulfonamide 218 N-(biphenyl-2-ylmethyl)-4-chloro-N- 469.7 [(3R)-2-oxoazepan-3-yl]benzenesulfonamide 219 4-chloro-N-(3-iodobenzyl)-N-[(3R)-2- 519.8 oxoazepan-3-yl]benzenesulfonamide 220 4-chloro-N-[3-(4- 503.8 fluorophenoxy)benzyl]-N-[(3R)-2-oxoazepan- 3-yl]benzenesulfonamide 221 4-chloro-N-(3,5-difluorobenzyl)-N- 429.8 [(3R)-2-oxoazepan-3-yl]benzenesulfonamide 222 4-chloro-N-(3,5-dimethoxybenzyl)-N- 453.7 [(3R)-2-oxoazepan-3-yl]benzenesulfonamide 223 4-chloro-N-(2-cyanobenzyl)-N-[(3R)-2- 440.9 oxoazepan-3-yl]benzenesulfonamide 224 4-chloro-N-(3,4-difluorobenzyl)-N- 429.9 [(3R)-2-oxoazepan-3-yl]benzenesulfonamide 225 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N- 547.7 {2- [(phenylsulfonyl)methyl]benzyl}benzene- sulfonamide 226 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N- 477.7 [4- (trifluoromethoxy)benzyl]benzenesulfonamide 227 4-chloro-N-(2-naphthylmethyl)-N-[(3R)- 443.7 2-oxoazepan-3-yl]benzenesulfonamide 228 N-Biphenyl-2-ylmethyl-4-chloro-N-(2- 469.7 oxo-azepan-3-yl)-benzenesulfonamide 229 4-chloro-N-(3-chlorobenzyl)-N-[(3R)-2- 427.8 oxoazepan-3-yl]benzenesulfonamide 230 4-chloro-N-(3-cyanobenzyl)-N-[(3R)-2- 418.8 oxoazepan-3-yl]benzenesulfonamide 231 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N- 477.8 [3- (trifluoromethoxy)benzyl]benzenesulfonamide 232 4-chloro-N-(4-fluorobenzyl)-N-[(3R)-2- 411.7 oxoazepan-3-yl]benzenesulfonamide 233 4-chloro-N-(2-chlorobenzyl)-N-[(3R)-2- 427.8 oxoazepan-3-yl]benzenesulfonamide 234 4-chloro-N-[(2E)-3,7-dimethylocta-2,6- 462 dien-1-yl]-N-[(3R)-2-oxoazepan-3- yl]benzenesulfonamide 235 4-Chloro-N-furan-2-ylmethyl-N-(2-oxo- 384.1 azepan-3-yl)-benzenesulfonamide 236 4-Chloro-N-furan-3-ylmethyl-N-(2-oxo- 384 azepan-3-yl)-benzenesulfonamide 237 4-Chloro-N-(4-cyano-benzyl)-N-(2-oxo- 419.1 azepan-3-yl)-benzenesulfonamide 238 4-Chloro-N-(3,4-dimethyl-benzyl)-N-(2- 422.1 oxo-azepan-3-yl)-benzenesulfonamide 239 4-Chloro-N-(2,5-dimethyl-benzyl)-N-(2- 422.1 oxo-azepan-3-yl)-benzenesulfonamide 240 4-Chloro-N-(1-dimethylamino-1H-pyrrol- 448.1 2-ylmethyl)-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 241 4-Chloro-N-(4-chloro-1-methyl-1H- 432 pyrazol-3-ylmethyl)-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 242 N-Benzofuran-2-ylmethyl-4-chloro-N-(2- 435.2 oxo-azepan-3-yl)-benzenesulfonamide 243 4-Chloro-N-(5-chloro-thiophen-2- 434 ylmethyl)-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 244 4-Chloro-N-(2-oxo-azepan-3-yl)-N- 457.1 (2,4,5-trimethyl-benzyl)- benzenesulfonamide 245 4-Chloro-N-(4-isopropyl-benzyl)-N-(2- 457.9 oxo-azepan-3-yl)-benzenesulfonamide 246 4-Chloro-N-(2-oxo-azepan-3-yl)-N- 458.2 (2,4,6-trimethyl-benzyl)- benzenesulfonamide 247 4-Chloro-N-(3-cyano-4-fluoro-benzyl)- 459.1 N-(2-oxo-azepan-3-yl)-benzenesulfonamide 248 4-Chloro-N-(4-dimethylamino-benzyl)-N- 437.1 (2-oxo-azepan-3-yl)-benzenesulfonamide 249 N-Benzo[1,3]dioxol-5-ylmethyl-4- 460.1 chloro-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 250 4-Chloro-N-(4-ethoxy-benzyl)-N-(2-oxo- 460.1 azepan-3-yl)-benzenesulfonamide 251 4-Chloro-N-(2-ethoxy-benzyl)-N-(2-oxo- 460.1 azepan-3-yl)-benzenesulfonamide 252 4-Chloro-N-(4-methoxy-2-methyl- 460 benzyl)-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 253 4-Chloro-N-(3-fluoro-4-methoxy- 464.1 benzyl)-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 254 4-Chloro-N-naphthalen-1-ylmethyl-N-(2- 444.1 oxo-azepan-3-yl)-benzenesulfonamide 255 4-Chloro-N-(2-oxo-azepan-3-yl)-N- 445.1 quinolin-2-ylmethyl-benzenesulfonamide 256 4-Chloro-N-(2-oxo-azepan-3-yl)-N- 445.1 quinolin-3-ylmethyl-benzenesulfonamide 257 4-Chloro-N-(2-oxo-azepan-3-yl)-N-(4- 462 oxo-4H-chromen-3-ylmethyl)- benzenesulfonamide 258 N-(4-Bromo-thiophen-2-ylmethyl)-4- 478.9 chloro-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 259

484.1 4-Chloro-N-(2-oxo-azepan-3-yl)-N-(2- piperidin-1-yl-thiazol-5-ylmethyl)- benzenesulfonamide 260 4-Chloro-N-(3,5-dimethyl-l-phenyl-1H- 488.1 pyrazol-4-ylmethyl)-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 261 4-Chloro-N-(2-oxo-azepan-3-yl)-N-(3- 514 phenoxy-thiophen-2-ylmethyl)- benzenesulfonamide 262 4-Chloro-N-(5-chloro-3-methyl-1- 508.1 phenyl-1H-pyrazol-4-ylmethyl)-N-(2-oxo- azepan-3-yl)-benzenesulfonamide 263 4-Chloro-N-(3,5-di-tert-butyl-4- 544.2 hydroxy-benzyl)-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 264 4-Chloro-N-(2-oxo-azepan-3-yl)-N-[1- 609 (toluene-4-sulfonyl)-1H-indol-3-ylmethyl]- benzenesulfonamide 265 4-Chloro-N-(3,5-dibromo-benzyl)-N-(2- 552 oxo-azepan-3-yl)-benzenesulfonamide 266 4-Chloro-N-(2,3-dimethoxy-benzyl)-N- 454.2 (2-oxo-azepan-3-yl)-benzenesulfonamide 267 4-Chloro-N-(3-fluoro-5- 479.9 trifluoromethyl-benzyl)-N-(2-oxo-azepan-3- yl)-benzenesulfonamide 268 4-Chloro-N-(6-chloro-imidazo[2,1- 474 b]thiazol-5-ylmethyl)-N-(2-oxo-azepan-3- yl)-benzenesulfonamide 269 4-Chloro-N-(4-methylsulfanyl-benzyl)- 462 N-(2-oxo-azepan-3-yl)-benzenesulfonamide 270 4-Chloro-N-(2,3-difluoro-benzyl)-N-(2- 430.1 oxo-azepan-3-yl)-benzenesulfonamide 270 4-Chloro-N-(5-ethyl-thiophen-2- 450.1 ylmethyl)-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 271 4-Chloro-N-(2-oxo-azepan-3-yl)-N-(3- 420.1 vinyl-benzyl)-benzenesulfonamide 272 4-Chloro-N-(2-fluoro-benzyl)-N-(2-oxo- 412.1 azepan-3-yl)-benzenesulfonamide 273 4-chloro-N-(3-methylbutyl)-N-[(3R)-2- 373.8 oxoazepan-3-yl]benzenesulfonamide 274 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N- 437.8 (3-phenoxypropyl)benzenesulfonamide 275 methyl 4-({[(4- 451.8 chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- yl]amino}methyl)benzoate 276 N-(2-bromobenzyl)-4-chloro-N-[(3R)-2- 472.7 oxoazepan-3-yl]benzenesulfonamide 277 N-(4-bromobenzyl)-4-chloro-N-[(3R)-2- 472.7 oxoazepan-3-yl]benzenesulfonamide 278 methyl 3-({[(4- 451.8 chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- yl]amino}methyl)benzoate 279 4-chloro-N-(2-methylbenzyl)-N-[(3R)-2- 407.8 oxoazepan-3-yl]benzenesulfonamide 280 4-Chloro-N-(4-fluoro-benzyl)-N-(2-oxo- 412.1 azepan-3-yl)-benzenesulfonamide 281 4-Chloro-N-(3-cyano-benzyl)-N-(2-oxo- 419.1 azepan-3-yl)-benzenesulfonamide 282 4-Chloro-N-(2-chloro-benzyl)-N-(2-oxo- 428 azepan-3-yl)-benzenesulfonamide 283 4-Chloro-N-(3-chloro-benzyl)-N-(2-oxo- 428 azepan-3-yl)-benzenesulfonamide 284 4-Chloro-N-(4-chloro-benzyl)-N-(2-oxo- 428.1 azepan-3-yl)-benzenesulfonamide 285 4-Chloro-N-(3,4-difluoro-benzyl)-N-(2- 430.1 oxo-azepan-3-yl)-benzenesulfonamide 286 4-Chloro-N-(2,4-difluoro-benzyl)-N-(2- 430.2 oxo-azepan-3-yl)-benzenesulfonamide 287 4-Chloro-N-(2-oxo-piperidin-3-yl)-N- 428 (3-phenyl-propyl)-benzenesulfonamide 288 4-Chloro-N-(2-methyl-3-phenyl-allyl)- 416 N-(2-oxo-piperidin-3-yl)- benzenesulfonamide 289 4-Chloro-N-(3,4-dimethoxy-benzyl)-N- 428 (2-oxo-piperidin-3-yl)-benzenesulfonamide 290 N-(4-Bromo-benzyl)-4-chloro-N-(2-oxo- 432 piperidin-3-yl)-benzenesulfonamide 291 4-Chloro-N-(2-oxo-piperidin-3-yl)-N- 462 (3-phenyl-allyl)-benzenesulfonamide 292 4-Chloro-N-(4-methoxy-benzyl)-N-(2- 459 oxo-piperidin-3-yl)-benzenesulfonamide 293 4-Chloro-N-(3-fluoro-4-methoxy- 408 benzyl)-N-(2-oxo-piperidin-3-yl)- benzenesulfonamide 294 4-Chloro-N-(2,4-difluoro-benzyl)-N-(2- 442 oxo-piperidin-3-yl)-benzenesulfonamide 295 4-Chloro-N-(3-fluoro-4-methoxy- 436 benzyl)-N-(2-oxo-pyrrolidin-3-yl)- benzenesulfonamide 296 4-Chloro-N-(2,4-difluoro-benzyl)-N-(2- 401 oxo-pyrrolidin-3-yl)-benzenesulfonamide 297 4-Chloro-N-(2-oxo-pyrrolidin-3-yl)-N- 414 (3-phenyl-allyl)-benzenesulfonamide 298 4-Chloro-N-(4-methoxy-benzyl)-N-(2- 418 oxo-pyrrolidin-3-yl)-benzenesulfonamide 299 4-Chloro-N-(3,4-dimethoxy-benzyl)-N- 448 (2-oxo-pyrrolidin-3-yl)-benzenesulfonamide 300 N-(4-Bromo-benzyl)-4-chloro-N-(2-oxo- 444 pyrrolidin-3-yl)-benzenesulfonamide 301 4-Chloro-N-(2-oxo-pyrrolidin-3-yl)-N- 393 (3-phenyl-propyl)-benzenesulfonamide 302 4-Chloro-N-(2-methyl-3-phenyl-allyl)- 428 N-(2-oxo-pyrrolidin-3-yl)- benzenesulfonamide 303 N-(3-Benzyloxy-propyl)-4-chloro-N-(2- 451.9 oxo-azepan-3-yl)-benzenesulfonamide 304 4-Chloro-N-(2-oxo-azepan-3-yl)-N-(4- 477.7 trifluoromethoxy-benzyl)- benzenesulfonamide 305 4-Chloro-N-(3,5-difluoro-benzyl)-N-(2- 429.8 oxo-azepan-3-yl)-benzenesulfonamide 306 4-Chloro-N-[3-(4-fluoro-phenoxy)- 503.8 benzyl]-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 307 4-Chloro-N-(8-hydroxy-octyl)-N-(2-oxo- 431.9 azepan-3-yl)-benzenesulfonamide 308 4-Chloro-N-(6-methyl-heptyl)-N-(2-oxo- 415.9 azepan-3-yl)-benzenesulfonamide 309 4-Chloro-N-(4-methyl-pentyl)-N-(2-oxo- 387.8 azepan-3-yl)-benzenesulfonamide 310 4-Chloro-N-[4-(1,3-dioxo-1,3-dihydro- 504.9 isoindol-2-yl)-butyl]-N-(2-oxo-azepan-3- yl)-benzenesulfonamide 311

357.7 N-But-3-enyl-4-chloro-N-(2-oxo-azepan- 3-yl)-benzenesulfonamide 312 4-Chloro-N-(2-oxo-azepan-3-yl)-N-prop- 341.8 2-ynyl-benzenesulfonamide 313 4-Chloro-N-[3-(1,3-dioxo-1,3-dihydro- 490.9 isoindol-2-yl)-propyl]-N-(2-oxo-azepan-3- yl)-benzenesulfonamide 314 4-Chloro-N-(3,5-dimethoxy-benzyl)-N- 453.7 (2-oxo-azepan-3-yl)-benzenesulfonamide 315 4-Chloro-N-(2-oxo-azepan-3-yl)-N-(3- 437.8 phenoxy-propyl)-benzenesulfonamide 316 4-Chloro-N-(6,7-dihydroxy-3,7- 475.6 dimethyl-octyl)-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 317 6-[(4-Chloro-benzenesulfonyl)-(2-oxo- 445.8 azepan-3-yl)-amino]-hexanoic acid ethyl ester 318

471.9 4-Chloro-N-dodecyl-N-(2-oxo-azepan-3- yl)-benzenesulfonamide 319 4-[(4-Chloro-benzenesulfonyl)-(2-oxo- 417.8 azepan-3-yl)-amino]-butyric acid ethyl ester 320 4-Chloro-N-[1,3]dioxolan-2-ylmethyl-N- 389.6 (2-oxo-azepan-3-yl)-benzenesulfonamide 321 4-Chloro-N-(2-oxo-azepan-3-yl)-N-(3- 477.8 trifluoromethoxy-benzyl)- benzenesulfonamide 322 N-(2-Benzenesulfonylmethyl-benzyl)-4- 547.7 chloro-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 323 4-Chloro-N-(2-oxo-azepan-3-yl)-N- 401.8 (tetrahydro-pyran-2-ylmethyl)- benzenesulfonamide 324 4-Chloro-N-(2-methoxy-ethyl)-N-(2-oxo- 361.8 azepan-3-yl)-benzenesulfonamide 325 4-Chloro-N-(2-oxo-azepan-3-yl)-N-(4- 451.8 phenoxy-butyl)-benzenesulfonamide 326 N-(4-Benzyloxy-butyl)-4-chloro-N-(2- 465.8 oxo-azepan-3-yl)-benzenesulfonamide 327 4-Chloro-N-{3-methoxy-4-[2-(4-methyl- 565.6 thiazol-5-yl)-ethoxy]-benzyl}-N-(2-oxo- azepan-3-yl)-benzenesulfonamide 328 5-[(4-Chloro-benzenesulfonyl)-(2-oxo- 431.8 azepan-3-yl)-amino]-pentanoic acid ethyl ester 329 4-Chloro-N-[2-(1,3-dioxo-1,3-dihydro- 476.9 isoindol-2-yl)-ethyl]-N-(2-oxo-azepan-3- yl)-benzenesulfonamide 330 4-Chloro-N-(3,7-dimethyl-oct-6-enyl)- 441.8 N-(2-oxo-azepan-3-yl)-benzenesulfonamide 331 4-Chloro-N-(2-oxo-azepan-3-yl)-N- 530.1 (3,7,11-trimethyl-dodeca-2,6,10-trienyl)- benzenesulfonamide 332 4-Chloro-N-decyl-N-(2-oxo-azepan-3- 443.9 yl)-benzenesulfonamide 333 4-Chloro-N-(3,7-dimethyl-octa-2,6- 462 dienyl)-N-(2-oxo-azepan-3-yl)- benzenesulfonamide 334 {2-[(4-Chloro-benzenesulfonyl)-(2-oxo- 427.1 azepan-3-yl)-amino]-ethyl}-carbamic acid methyl ester 335 {2-[(4-Chloro-benzenesulfonyl)-(2-oxo- 483.2 azepan-3-yl)-amino]-1-methyl-ethyl}- carbamic acid tert-butyl ester 336 4-Chloro-N-(2-cyano-benzyl)-N-(2-oxo- 440.9 azepan-3-yl)-benzenesulfonamide 337 3-[(4-Chloro-benzenesulfonyl)-(2-oxo- 375.8 azepan-3-yl)-amino]-propionic acid 338 2-[(4-Chloro-benzenesulfonyl)-(2-oxo- 360.7 azepan-3-yl)-amino]-acetamide

The following compounds can be prepared essentially according to the methods and procedures described above.

339 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N-[(2-oxo-2,3- dihydro-1H-benzimidazol-5-yl)methyl]benzenesulfonamide 340 4-chloro-N-[(1,2-dimethyl-1H-benzimidazol-6-yl)methyl]- N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 341 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N-[(3-oxo-1,3- dihydro-2,1-benzisoxazol-6-yl)methyl]benzensulfonamide 342 4-chloro-N-[(2,3-dimethyl-2,3-dihydro-1,3-benzoxazol-5- yl)methyl]-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 343

4-chloro-N-[(1-methyl-1H-indazol-5-yl)methyl]-N-[(3R)- 2-oxoazepan-3-yl]benzenesulfonamide 344 4-chloro-N-(furo[3,2-b]pyridin-5-ylmethyl)-N-[(3R)-2- oxoazepan-3-yl]benzenesulfonamide 345 N-(2,1,3-benzoxadiazol-5-ylmethyl)-4-chloro-N-[(3R)-2- oxoazepan-3-yl]benzenesulfonamide 346 4-chloro-N-[(3,3-dimethyl-3H-indazol-6-yl)methyl]-N- [(3R)-2-oxoazepan-3-yl]benzenesulfonamide 347 4-chloro-N-[(1,3-dimethyl-1H-pyrazolo[3,4-c]pyridin-5- yl)methyl]-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 348 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N-(quinoxalin-6- ylmethyl)benzenesulfonamide 349 4-chloro-N-[(3-oxido-1,4-dihydro-2,3,1,4- benzoxathiadiazin-6-yl)methyl]-N-[(3R)-2-oxoazepan-3- yl]benzenesulfonamide 350 4-chloro-N-[(1-ethoxy-1H-1,2,3-benzotriazol-5- yl)methyl]-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 351 4-chloro-N-[(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5- yl)methyl]-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 352 4-chloro-N-(isoquinolin-7-ylmethyl)-N-[(3R)-2- oxoazepan-3-yl]benzenesulfonamide 353 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N-(quinolin-6- ylmethyl)benzenesulfonamide 354 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N-(quinolin-7- ylmethyl)benzenesulfonamide 355 4-chloro-N-(isoquinolin-6-ylmethyl)-N-[(3R)-2- oxoazepan-3-yl]benzenesulfonamide

The following compounds are prepared essentially according to the methods and procedures described above.

Cmpnd No. Name M + H M + Na 356 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N-[(1-phenyl-1H- 460 — 1,2,3-triazol-4-yl)methyl]benzenesulfonamide 357 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N-[(2- 483 — piperidin-1-yl-1,3-thiazol-5-yl)methyl]benzenesulfonamide 358 4-chloro-N-[(6-methoxypyridin-3- 424 — yl)methyl]-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 359 N-[(6-bromopyridin-2-yl)methyl]-4-chloro- 473.9 — N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 360 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N- 420 — [(2E)-3-pyridin-3-ylprop-2-en-1-yl]benzenesulfonamide 361 4-chloro-N-[(1-methyl-1H-indol-2- — 468 yl)methyl]-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 362 4-chloro-N-[(5-chloro-1,3-dimethyl-1H- 444.9 — pyrazol-4-yl)methyl]-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 363 4-chloro-N-[(1,3-dimethyl-1H-pyrazol-5- 410.9 — yl)methyl]-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 364 4-chloro-N-[(6-chloropyridin-3- 427.9 — yl)methyl]-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 365 4-chloro-N-[(3-methyl-1-benzothien-2- — 484.9 yl)methyl]-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 366 4-chloro-N-{[5-cyano-6-(methylthio)pyridin-2- 464.9 — yl]methyl}-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 367 N-[(6-bromopyridin-3-yl)methyl]-4-chloro- 473.9 — N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 368 4-chloro-N-[(1-methyl-1H-imidazol-2- 396.9 — yl)methyl]-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 369

— 475.9 methyl 5-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan- 3-yl]amino}methyl)-1-methyl-1H-pyrrole-2-carboxylate 370 4-chloro-N-[(1-methyl-1H-pyrrol-2- — 417.9 yl)methyl]-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 371 4-chloro-N-[(6-methylpyridin-2- 407.9 — yl)methyl]-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 372 N-[(1-benzyl-1H-indol-3-yl)methyl]-4- — 544 chloro-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 373 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N- 399.9 — (1,3-thiazol-2-ylmethyl)benzenesulfonamide 374 4-chloro-N-[(5-methyl-2-furyl)methyl]-N- — 418.9 [(3R)-2-oxoazepan-3-yl]benzenesulfonamide 375 4-chloro-N-[(5-methyl-2-thienyl)methyl]- — 434.9 N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 376 4-chloro-N-[(2-methyl-1H-imidazol-4- 397 — yl)methyl]-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 377 4-chloro-N-{[5-(methylthio)-2- — 466.9 thienyl]methyl}-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 378 4-chloro-N-[(5-chloro-2-furyl)methyl]-N- — 438.9 [(3R)-2-oxoazepan-3-yl]benzenesulfonamide 379 N-[(5-bromo-2-furyl)methyl]-4-chloro-N- — 484.8 [(3R)-2-oxoazepan-3-yl]benzenesulfonamide 380 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N-[(6- 477 — piperidin-1-ylpyridin-3-yl)methyl]benzenesulfonamide 381 4-chloro-N-[(6-morpholin-4-ylpyridin-3- 479 — yl)methyl]-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 382 4-chloro-N-[(1-methyl-1H-indol-3- — 468 yl)methyl]-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 383 4-chloro-N-[(2-ethyl-1H-imidazol-5- 411 — yl)methyl]-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 384 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N-[(2- 459 — phenyl-1H-imidazol-5-yl)methyl]benzenesulfonamide 385 N-[(2-butyl-1H-imidazol-4-yl)methyl]-4- 439 — chloro-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 386 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N-{[6- 462 — (trifluoromethyl)pyridin-3-yl]methyl}benzenesulfonamide 387 4-chloro-N-(1H-imidazol-5-ylmethyl)-N- 383 — [(3R)-2-oxoazepan-3-yl]benzenesulfonamide 388 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N- 400.9 — (1,2,3-thiadiazol-4-ylmethyl)benzenesulfonamide 389 4-chloro-N-(1H-imidazol-2-ylmethyl)-N- 383 — [(3R)-2-oxoazepan-3-yl]benzenesulfonamide 390 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N- 399.9 — (1,3-thiazol-5-ylmethyl)benzenesulfonamide 391 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N-(1H- — 403.9 pyrrol-2-ylmethyl)benzenesulfonamide 392 4-chloro-N-[(2-chloro-1,3-thiazol-5- 433.9 — yl)methyl]-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 393 4-chloro-N-{[2-(diethylamino)-1,3- 471 — thiazol-5-yl]methyl}-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 394 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N- 444 — (quinolin-3-ylmethyl)benzenesulfonamide 395 4-chloro-N-[(5-chloro-1,2,4-thiadiazol-3- 435 — yl)methyl]-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 396 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N-[4- 460 — (1H-1,2,4-triazol-1-yl)benzyl]benzenesulfonamide 397

491 — 4-chloro-N-{[5-(4-methoxyphenyl)-1,3,4- oxadiazol-2-yl]methyl}-N-[(3R)-2-oxoazepan-3- yl]benzenesulfonamide 398 4-chloro-N-[2-fluoro-5-(trifluoromethyl)benzyl]- 479 — N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 399 4-chloro-N-{[5-(3,5-dimethylisoxazol-4-yl)-1,2,4- 480 — oxadiazol-3-yl]methyl}-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 400 4-chloro-N-({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3- 558 — thiazol-5-yl}methyl)-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 401 4-chloro-N-({5-[2-(methylthio)pyridin-3-yl]-1,2,4- 508 — oxadiazol-3-yl}methyl)-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 402 4-chloro-N-(3-fluoro-4-methylbenzyl)-N- 425 — [(3R)-2-oxoazepan-3-yl]benzenesulfonamide 403 4-chloro-N-[(1-methyl-1H-1,2,3-benzotriazol-5- 448 — yl)methyl]-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 404 4-chloro-N-[(5-methylisoxazol-3- 398 — yl)methyl]-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 405 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N- 482.9 — (pentafluorobenzyl)benzenesulfonamide 406 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N- 400 — {[(2S)-5-oxopyrrolidin-2-yl]methyl}benzenesulfonamide 407 5-({[(4-chlorophenyl)sulfonyl][(3R)-2- 518 — oxoazepan-3-yl]amino}methyl)-N-phenylthiophene-2-carboxamide 408 5-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 522 — yl]amino}methyl)-N-(2-furylmethyl)thiophene-2-carboxamide 409 5-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 539 — yl]amino}methyl)-N-(1-methylpiperidin-4-yl)thiophene-2-carboxamide 410 5-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 546 — yl]amino}methyl)-N-[(1R)-1-phenylethyl]thiophene-2-carboxamide 411 5-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan- 547 — 3-yl]amino}methyl)-N-(2-pyridin-3-ylethyl)thiophene-2-carboxamide 412 5-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan- 546 — 3-yl]amino}methyl)-N-[(1S)-1-phenylethyl]thiophene-2-carboxamide 413 N-butyl-5-({[(4-chlorophenyl)sulfonyl][(3R)- 498 — 2-oxoazepan-3-yl]amino}methyl)thiophene-2-carboxamide 414 5-({[(4-chlorophenyl)sulfonyl][(3R)-2- 467 — oxoazepan-3-yl]amino}methyl)-N-cyclopropyl-2-furamide 415 5-({[(4-chlorophenyl)sulfonyl][(3R)-2- 506 — oxoazepan-3-yl]amino}methyl)-N-(2-furylmethyl)-2-furamide 416 5-({[(4-chlorophenyl)sulfonyl][(3R)-2- 523 — oxoazepan-3-yl]amino}methyl)-N-(1-methylpiperidin-4-yl)-2-furamide 417 5-({[(4-chlorophenyl)sulfonyl][(3R)-2- 530 — oxoazepan-3-yl]amino}methyl)-N-[(1R)-1-phenylethyl]-2-furamide 418 5-({[(4-chlorophenyl)sulfonyl][(3R)-2- 531 — oxoazepan-3-yl]amino}methyl)-N-(2-pyridin-3-ylethyl)-2-furamide 419 N-butyl-5-({[(4-chlorophenyl)sulfonyl][(3R)- 482 — 2-oxoazepan-3-yl]amino}methyl)-2-furamide 420 N-benzyl-5-({[(4-chlorophenyl)sulfonyl][(3R)- 516 — 2-oxoazepan-3-yl]amino}methyl)-2-furamide 421 N-(4-benzoylbenzyl)-4-chloro-N-[(3R)-2- 496.8 — oxoazepan-3-yl]benzenesulfonamide 422 N-(2-aminoethyl)-4-({[(4-chlorophenyl)sulfonyl][(3R)- 479 — 2-oxoazepan-3-yl]amino}methyl)benzamide 423 tert-butyl 4-({[(4-chlorophenyl)sulfonyl][(3R)- — 522 2-oxoazepan-3-yl]amino}methyl)piperidine-1-carboxylate The following compounds are prepared essentially according to the methods and procedures described above.

Cmpnd. No. Name M + H M + Na 424 4-chloro-N-(4-nitrobenzyl)-N-[(3R)-2- 437.0 — oxoazepan-3-yl]benzenesulfonamide 425 ethyl (2E)-4-{[(4-chlorophenyl)sulfonyl][(3R)-2- 429.0 — oxoazepan-3-yl]amino}-3-methylbut-2-enoate 426 ethyl 2-({[(4-chlorophenyl)sulfonyl][(3R)-2- 429.0 — oxoazepan-3-yl]amino}methyl)cyclopropanecarboxylate 427 methyl 6-{[(4-chlorophenyl)sulfonyl][(3R)-2- 431.0 — oxoazepan-3-yl]amino}hexanoate 428 4-chloro-N-(cyclopropylmethyl)-N- 357.0 — [(3R)-2-oxoazepan-3-yl]benzenesulfonamide 429 4-chloro-N-[4-(methylthio)benzyl]-N- — 460.9 [(3R)-2-oxoazepan-3-yl]benzenesulfonamide 430 4-chloro-N-[4-(methylsulfinyl)benzyl]- 454.9 — N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 431 4-chloro-N-[4-(methylsulfonyl)benzyl]- 470.9 — N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 432 N-(4-aminobenzyl)-4-chloro-N-[(3R)-2- — 429.9 oxoazepan-3-yl]benzenesulfonamide 433 N-[4-({[(4-chlorophenyl)sulfonyl][(3R)- — 533.9 2-oxoazepan-3-yl]amino]methyl)phenyl]benzamide 434 N-[4-({[(4-chlorophenyl)sulfonyl][(3R)- — 500.0 2-oxoazepan-3-yl]amino}methyl)phenyl]butanamide 435 N-[4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan- — 540.0 3-yl]amino]methyl)phenyl]cyclohexanecarboxamide 436 N-[4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan- — 535.0 3-yl]amino}methyl)phenyl]pyridine-2-carboxamide 437 N-[4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan- — 536.0 3-yl]amino}methyl)phenyl]pyrazine-2-carboxamide 438 methyl [4-({[(4-chlorophenyl)sulfonyl][(3R)-2- — 488.0 oxoazepan-3-yl]amino}methyl)phenyl]carbamate 439 phenyl [4-({[(4-chlorophenyl)sulfonyl][(3R)-2- — 550.0 oxoazepan-3-yl]amino}methyl)phenyl]carbamate 440 isopropyl [4-({[(4-chlorophenyl)sulfonyl][(3R)-2- — 515.9 oxoazepan-3-yl]amino}methyl)phenyl]carbamate 441 4-chloro-N-(4-{[(methylamino)carbonyl]amino}benzyl)-N- — 487.0 [(3R)-2-oxoazepan-3-yl]benzenesulfonamide 442 4-chloro-N-(4-{[(isopropylamino)carbonyl]amino}benzyl)- — 515.0 N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 443 N-{4-[(anilinocarbonyl)amino[benzyl}- — 549.0 4-chloro-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 444 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N-[4-({[(2- — 577.0 phenylethyl)amino]carbonyl}amino)benzyl]benzenesulfonamide 445 4-chloro-N-[4-({[(3,5-dimethylisoxazol-4- — 568.0 yl)amino]carbonyl}amino)benzyl]-N-[(3R)-2- oxoazepan-3-yl]benzenesulfonamide 446 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 506.1 — yl]amino}methyl)-N-(2,2-dimethylpropyl)benzamide 447 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 533.0 — yl]amino}methyl)-N-(1-methylpiperidin-4-yl)benzamide 448 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 554.0 — yl]amino}methyl)-N-(1-methyl-1-phenylethyl)benzamide 449 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 541.0 — yl]amino}methyl)-N-(2-pyridin-3-ylethyl)benzamide 450 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3-yl]amino} 544.0 — methyl)-N-[(1,5-dimethyl-1H-pyrazol-3-yl)methyl]benzamide 451 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 490.0 — yl]amino}methyl)-N-(2-methylprop-2-en-1-yl)benzamide 452 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 492.0 — yl]amino}methyl)-N,N-diethylbenzamide 453 N-[2-(tert-butylthio)ethyl]-4-({[(4-chlorophenyl)sulfonyl][(3R)- 552.0 — 2-oxoazepan-3-yl]amino}methyl)benzamide 454 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 532.0 — yl]amino}methyl)-N-(4-methylcyclohexyl)benzamide 455 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 490.0 — yl]amino}methyl)-N-cyclobutylbenzamide 456 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 504.0 — yl]amino}methyl)-N-cyclopentylbenzamide 457 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 552.0 — yl]amino}methyl)-N-(2,3-dihydro-1H-inden-2-yl)benzamide 458 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 476.0 — yl]amino}methyl)-N-cyclopropylbenzamide 459 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 521.1 — yl]amino}methyl)-N-[2-(dimethylamino)-1-methylethyl]benzamide 460 4-({[(4-chlorophenyl)sulfonyl]p(3R)-2-oxoazepan-3- 519.9 — yl]amino}methyl)-N-(2-oxotetrahydrofuran-3-yl)benzamide 461 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 552.0 — yl]amino}methyl)-N-(2,3-dihydro-1H-inden-1-yl)benzamide 462 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 577.0 — yl]amino}methyl)-N-[4-(diethylamino)-1-methylbutyl]benzamide 463 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 533.1 — yl]amino}methyl)-N-(2-pyrrolidin-1-ylethyl)benzamide 464 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 506.0 — yl]amino}methyl)-N-(2-methylbutyl)benzamide 465 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 522.0 — yl]amino}methyl)-N-(2-isopropoxyethyl)benzamide 466 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 518.0 — yl]amino}methyl)-N-cyclohexylbenzamide 467 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 524.0 — yl]amino}methyl)-N-[3-(methylthio)propyl]benzamide 468 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 516.0 — yl]amino}methyl)-N-(2-furylmethyl)benzamide 469 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 554.0 — yl]amino}methyl)-N-(3-phenylpropyl)benzamide 470 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 524.1 — yl]amino}methyl)-N-[2-(2-hydroxyethoxy)ethyl]benzamide 471 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 513.0 — yl]amino}methyl)-N-pyridin-3-ylbenzamide 472 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 478.0 — yl]amino}methyl)-N-propylbenzamide 473 N-butyl-4-({[(4-chlorophenyl)sulfonyl][(3R)-2- 492.0 — oxoazepan-3-yl]amino]methyl)benzamide 474 N-benzyl-4-({[(4-chlorophenyl)sulfonyl][(3R)-2- 526.0 — oxoazepan-3-yl]amino}methyl)benzamide 475 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 562.0 — yl]amino}methyl)-N-(3,5-difluorobenzyl)benzamide 476 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 540.0 — yl]amino}methyl)-N-(1-phenylethyl)benzamide 477 4-chloro-N-{4-[(2,5-dimethyl-2,5-dihydro-1H-pyrrol-1- 516.0 — yl)carbonyl]benzyl}-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 478 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N- 490.0 — [4-(pyrrolidin-1-ylcarbonyl)benzyl]benzenesulfonamide 479 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 478.0 — yl]amino}methyl)-N-isopropylbenzamide 480 N-(tert-butyl)-4-({[(4-chlorophenyl)sulfonyl][(3R)-2- 492.0 — oxoazepan-3-yl]amino]methyl)benzamide 481 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 556.0 — yl]amino}methyl)-N-(2-hydroxy-2-phenylethyl)benzamide 482 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 532.1 — yl]amino}methyl)-N-cyclohexyl-N-methylbenzamide 483 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 540.0 — yl]amino}methyl)-N-(2-phenylethyl)benzamide 484 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 518.9 — yl]amino}methyl)-N-1,3-thiazol-2-ylbenzamide 485 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 512.0 — yl]amino}methyl)-N-phenylbenzamide 486 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 492.0 — yl]amino}methyl)-N-isobutylbenzamide 487 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 532.1 — yl]amino}methyl)-N-(2-methylcyclohexyl)benzamide 488 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 518.1 — yl]amino}methyl)-N-cyclopentyl-N-methylbenzamide 489 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 520.1 — yl]amino}methyl)-N,N-diisopropylbenzamide 490 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 542.0 — yl]amino}methyl)-N-[(5-methylpyrazin-2-yl)methyl]benzamide 491 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 534.0 — yl]amino}methyl)-N-(4-hydroxycyclohexyl)benzamide 492 4-chloro-N-(cyanomethyl)-N-[(3R)-2-oxoazepan-3- 342.0 — yl]benzenesulfonamide 493 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N-[4-(4,4,5,5-tetramethyl- 519.0 — 1,3,2-dioxaborolan-2-yl)benzyl]benzenesulfonamide 494 tert-butyl [4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan- — 548.0 3-yl]amino}methyl)-2-fluorophenyl]carbamate 495 N-benzyl-2-[4-({[(4-chlorophenyl)sulfonyl][(3R)-2- 540.0 — oxoazepan-3-yl]amino}methyl)phenyl]acetamide 496 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N-[4-(2-oxo-2-pyrrolidin-1- 504.0 — ylethyl)benzyl]benzenesulfonamide 497 2-[4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 576.0 — yl]amino}methyl)phenyl]-N-(3,5-difluorobenzyl)acetamide 498 2-[4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- — 568.0 yl]amino}methyl)phenyl]-N-cyclohexylpropanamide 499 2-[4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- — 570.0 yl]amino}methyl)phenoxy]-N-cyclohexylacetamide 500 N-benzyl-2-[4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- — 578.0 yl]amino}methyl)phenoxy]acetamide 501 N-[4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- — 566.0 yl]amino}methyl)-2-fluorophenyl]-2-phenylacetamide 502 N-[4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- — 552.0 yl]amino}methyl)-2-fluorophenyl]benzamide 503 N-[4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- — 518.0 yl]amino}methyl)-2-fluorophenyl]butanamide 504 N-[4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- — 553.0 yl]amino}methyl)-2-fluorophenyl]pyridine-2-carboxamide 505 N-[4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- — 594.0 yl]amino}methyl)-2-fluorophenyl]-4-phenylbutanamide 506 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan- 570.0 — 3-yl]amino}methyl)-N-[(1R)-1-(4-methoxyphenyl)ethyl]benzamide 507 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 558.0 — yl]amino}methyl)-N-[(1R)-1-(4-fluorophenyl)ethyl]benzamide 508 4-chloro-N-{4-[(6-fluoro-2-methyl-3,4-dihydroquinolin-1(2H)- 584.0 — yl)carbonyl]benzyl}-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 509 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 532.0 — yl]amino}methyl)-N-(2-thienylmethyl)benzamide 510 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 522.0 — yl]amino}methyl)-N-[1-(methoxymethyl)propyl]benzamide 511 ethyl 4-{[4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan- 591.0 — 3-yl]amino}methyl)benzoyl]amino}piperidine-1-carboxylate 512 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 568.0 — yl]amino}methyl)-N-[(1S,2R)-2-yl]benzamide 513 N-[(1S)-2-(benzyloxy)-1-(hydroxymethyl)ethyl]-4-({[(4- 599.0 — chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- yl]amino}methyl)benzamide 514 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 556.0 — yl]amino}methyl)-N-[(1R)-2-hydroxy-1-phenylethyl]benzamide 515 4-chloro-N-[4-(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)benzyl]- 552.0 — N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 516 N-(4-{[(2S)-2-(anilinomethyl)pyrrolidin-1-yl]carbonyl} 595.0 — benzyl)-4-chloro-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 517 N-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-4-({[(4-chlorophenyl) 572.0 — sulfonyl][(3R)-2-oxoazepan-3-yl]amino}methyl)benzamide 518 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 568.0 — yl]amino}methyl)-N-[3-(2-furyl)-1H-pyrazol-5-yl]benzamide 519 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3-yl]amino} 665.0 — methyl)-N-[2-morpholin-4-yl-5-(trifluoromethyl)phenyl]benzamide 520 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 577.0 — yl]amino}methyl)-N-[2-(1H-pyrrol-1-yl)phenyl]benzamide 521 N-(4-acetylphenyl)-4-({[(4-chlorophenyl)sulfonyl][(3R)- 554.0 — 2-oxoazepan-3-yl]amino}methyl)benzamide 522 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 578.0 — yl]amino}methyl)-N-(3-phenyl-1H-pyrazol-5-yl)benzamide 523 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 578.0 — yl]amino}methyl)-N-(1-phenyl-1H-pyrazol-5-yl)benzamide 524 N-(5-tert-butylisoxazol-3-yl)-4-({[(4-chlorophenyl)sulfonyl][(3R)- 559.0 — 2-oxoazepan-3-yl]amino}methyl)benzamide 525 N-(6-bromopyridin-2-yl)-4-({[(4-chlorophenyl)sulfonyl][(3R)- 593.0 — 2-oxoazepan-3-yl]amino}methyl)benzamide 526 N-benzyl-4-({[(3,5-difluorophenyl)sulfonyl][(3R)- 528.0 — 2-oxoazepan-3-yl]amino}methyl)benzamide 527 N-benzyl-4-({[(3-chlorophenyl)sulfonyl][(3R)- 526.0 — 2-oxoazepan-3-yl]amino}methyl)benzamide 528

528.0 — N-benzyl-4-({[(3,4-difluorophenyl)sulfonyl][(3R)- 2-oxoazepan-3-yl]amino}methyl)benzamide 529 N-benzyl-4-({[(3-chloro-4-fluorophenyl)sulfonyl][(3R)- 544.0 — 2-oxoazepan-3-yl]amino}methyl)benzamide 530 N-benzyl-4-({[(4-fluorophenyl)sulfonyl][(3R)- 510.0 — 2-oxoazepan-3-yl]amino}methyl)benzamide 531 4-({[(3,5-difluorophenyl)sulfonyl][(3R)- 438.0 — 2-oxoazepan-3-yl]amino}methyl)benzamide 532 4-({[(3-chlorophenyl)sulfonyl][(3R)-2- 436.0 — oxoazepan-3-yl]amino}methyl)benzamide 533 4-({[(4-chlorophenyl)sulfonyl][(3R)-2- 437.0 — oxoazepan-3-yl]amino}methyl)benzoic acid 534 4-({[(4-chlorophenyl)sulfonyl][(3R)-2- 436.0 — oxoazepan-3-yl]amino}methyl)benzamide 535 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 540.0 — yl]amino}methyl)-N-[(1S)-1-phenylethyl]benzamide 536 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 570.0 — yl]amino}methyl)-N-[(1S,2R)-2-hydroxy-1-methyl- 2-phenylethyl]benzamide 537 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 540.0 — yl]amino}methyl)-N-[(1R)-1-phenylethyl]benzamide 538 N-(3-chloro-2,6-difluorobenzyl)-4-({[(4-chlorophenyl) 596.0 — sulfonyl][(3R)-2-oxoazepan-3-yl]amino}methyl)benzamide 539 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 576.0 — yl]amino}methyl)-N-(1-naphthylmethyl)benzamide 540 4-chloro-N-{4-[(3-methylpiperazin-1-yl)carbonyl]benzyl}-N- 519.0 — [(3R)-2-oxoazepan-3-yl]benzenesulfonamide 541 N-(1-benzylpiperidin-3-yl)-4-({[(4-chlorophenyl) 609.2 — sulfonyl][(3R)-2-oxoazepan-3-yl]amino}methyl)benzamide 542 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 568.0 — yl]amino}methyl)-N-(4-isopropylbenzyl)benzamide 543 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 494.0 — yl]amino}methyl)-N-(2-hydroxy-1-methylethyl)benzamide 544 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 541.0 — yl]amino}methyl)-N-(1-pyridin-4-ylethyl)benzamide 545 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 544.0 — yl]amino}methyl)-N-(4-fluorobenzyl)benzamide 546 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 586.0 — yl]amino}methyl)-N-(2,5-dimethoxybenzyl)benzamide 547 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 519.0 — yl]amino}methyl)-N-piperidin-3-ylbenzamide 548 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 528.0 — yl]amino}methyl)-N-(pyrazin-2-ylmethyl)benzamide 549 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 554.0 — yl]amino}methyl)-N-(3,5-dimethylbenzyl)benzamide 550 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 594.0 — yl]amino}methyl)-N-(2,6-dichlorobenzyl)benzamide 551 N-(5-chloro-2-methylbenzyl)-4-({[(4-chlorophenyl) 574.0 — sulfonyl][(3R)-2-oxoazepan-3-yl]amino}methyl)benzamide 552 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 554.0 — yl]amino}methyl)-N-[(1S)-1-phenylpropyl]benzamide 553 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 554.0 — yl]amino}methyl)-N-[(1R)-1-phenylpropyl]benzamide 554 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 540.0 — yl]amino}methyl)-N-(3-methylbenzyl)benzamide 555 N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-({[(4-chlorophenyl) 545.0 — sulfonyl][(3R)-2-oxoazepan-3-yl]amino}methyl)benzamide 556 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 610.0 — yl]amino}methyl)-N-[3-(trifluoromethoxy)benzyl]benzamide 557 N-(biphenyl-3-ylmethyl)-4-({[(4-chlorophenyl) 602.0 — sulfonyl][(3R)-2-oxoazepan-3-yl]amino}methyl)benzamide 558 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 530.0 — yl]amino}methyl)-N-[(5-methyl-2-furyl)methyl]benzamide 559 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 592.0 — yl]amino}methyl)-N-[4-(1H-pyrazol-1-yl)benzyl]benzamide 560 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 572.0 — yl]amino}methyl)-N-[4-(methylthio)benzyl]benzamide 561 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3-yl]amino} 566.0 — methyl)-N-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]benzamide 562 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 554.0 — yl]amino}methyl)-N-(2,5-dimethylbenzyl)benzamide 563 N-[(1R)-1-(3-bromophenyl)ethyl]-4-({[(4-chlorophenyl) 620.0 — sulfonyl][(3R)-2-oxoazepan-3-yl]amino}methyl)benzamide 564 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 570.0 — yl]amino}methyl)-N-[(1S)-1-(4-methoxyphenyl)ethyl]benzamide 565 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 570.0 — yl]amino}methyl)-N-[(1S)-1-(3-methoxyphenyl)ethyl]benzamide 566 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 552.0 — yl]amino}methyl)-N-[(1S)-2,3-dihydro-1H-inden-1-yl]benzamide 567 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 529.0 — yl]amino}methyl)-N-(2-cyanoethyl)-N-cyclopropylbenzamide 568 N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4-({[(4-chlorophenyl) 545.0 — sulfonyl][(3R)-2-oxoazepan-3-yl]amino}methyl)benzamide 569 N-(3-chloro-2-methylbenzyl)-4-({[(4-chlorophenyl) 574.0 — sulfonyl][(3R)-2-oxoazepan-3-yl]amino}methyl)benzamide 570 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 562.0 — yl]amino}methyl)-N-(2,6-difluorobenzyl)benzamide 571 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 531.0 — yl]amino}methyl)-N-[(5-methylisoxazol-3-yl)methyl]benzamide 572 N-(1-benzothien-3-ylmethyl)-4-({[(4-chlorophenyl) 582.0 — sulfonyl][(3R)-2-oxoazepan-3-yl]amino}methyl)benzamide 573 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 594.0 — yl]amino}methyl)-N-(2,3-dichlorophenyl)benzamide 574 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 591.0 — yl]amino}methyl)-N-[3-(1H-pyrrol-1-yl)benzyl]benzamide 575 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 570.0 — yl]amino}methyl)-N-(2-ethoxybenzyl)benzamide 576 N-(6-chloro-2-fluoro-3-methylbenzyl)-4-({[(4-chlorophenyl) 592.0 — sulfonyl][(3R)-2-oxoazepan-3-yl]amino}methyl)benzamide 577 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 554.0 — yl]amino}methyl)-N-methyl-N-[(1R)-1-phenylethyl]benzamide 578 N-(1-benzylpiperidin-4-yl)-4-({[(4-chlorophenyl) 609.0 — sulfonyl][(3R)-2-oxoazepan-3-yl]amino}methyl)benzamide 579 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 610.0 — yl]amino}methyl)-N-[2-(trifluoromethoxy)benzyl]benzamide 580 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 554.0 — yl]amino}methyl)-N-(2,3-dimethylbenzyl)benzamide 581 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 562.0 — yl]amino}methyl)-N-(2,5-difluorobenzyl)benzamide 582 N-(3-bromo-4-fluorobenzyl)-4-({[(4-chlorophenyl) 622.0 — sulfonyl][(3R)-2-oxoazepan-3-yl]amino}methyl)benzamide 583 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 612.0 — yl]amino}methyl)-N-[4-fluoro-3-(trifluoromethyl)benzyl]benzamide 584 N-(3-chloro-4-fluorobenzyl)-4-({[(4-chlorophenyl) 578.0 — sulfonyl][(3R)-2-oxoazepan-3-yl]amino}methyl)benzamide 585 N-[(1S,2S)-2-(benzyloxy)cyclopentyl]-4-({[(4-chlorophenyl) 610.0 — sulfonyl][(3R)-2-oxoazepan-3-yl]amino}methyl)benzamide 586 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 541.0 — yl]amino}methyl)-N-methyl-N-(pyridin-3-ylmethyl)benzamide 587 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 558.0 — yl]amino}methyl)-N-(3,4-dihydroxybenzyl)benzamide 588 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 572.0 — yl]amino}methyl)-N-(4-hydroxy-3-methoxybenzyl)benzamide 589 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 587.0 — yl]amino}methyl)-N-{[3-hydroxy-5- (hydroxymethyl)-2-methylpyridin-4-yl]methyl}benzamide 590 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 544.0 — yl]amino}methyl)-N-(3-fluorobenzyl)benzamide 591 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 534.0 — yl]amino}methyl)-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide 592 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 566.0 — yl]amino}methyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)benzamide 593 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 527.0 — yl]amino}methyl)-N-(pyridin-3-ylmethyl)benzamide 594 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 527.0 — yl]amino}methyl)-N-(pyridin-4-ylmethyl)benzamide 595 N-(2-chlorobenzyl)-4-({[(4-chlorophenyl) 560.0 — sulfonyl][(3R)-2-oxoazepan-3-yl]amino}methyl)benzamide 596 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3-yl]amino} 568.0 — methyl)-N-[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]benzamide 597 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 540.0 — yl]amino}methyl)-N-(2-methylbenzyl)benzamide 598 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 506.0 — yl]amino}methyl)-N-[(3R)-tetrahydrofuran-3-yl]benzamide 599 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3-yl]amino} 546.0 — methyl)-N-[(1R,6S)-6-(hydroxymethyl)cyclohex-3-en-1-yl]benzamide 600 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 594.0 — yl]amino}methyl)-N-[4-(trifluoromethyl)benzyl]benzamide 601 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 586.0 — yl]amino}methyl)-N-(3,4-dimethoxybenzyl)benzamide 602 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 551.0 — yl]amino}methyl)-N-[cyano(phenyl)methyl]benzamide 603 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 594.0 — yl]amino}methyl)-N-(3,5-dichlorobenzyl)benzamide 604 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 610.0 — yl]amino}methyl)-N-[4-(trifluoromethoxy)benzyl]benzamide 605 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 604.0 — yl]amino}methyl)-N-[4-(methylsulfonyl)benzyl]benzamide 606 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 596.0 — yl]amino}methyl)-N-(3,4-dichlorobenzyl)benzamide 607 N-(4-chlorobenzyl)-4-({[(4-chlorophenyl) 560.0 — sulfonyl][(3R)-2-oxoazepan-3-yl]amino}methyl)benzamide 608 4-chloro-N-(4-{[(2S)-2-(hydroxymethyl)pyrrolidin-1- 520.0 — yl]carbonyl}benzyl)-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 609 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 546.2 — yl]amino}methyl)-N-cyclohexyl-N-ethylbenzamide 610 4-chloro-N-(4-{[2-(hydroxymethyl)piperidin-1- 534.0 — yl]carbonyl}benzyl)-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 611 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N-(4-{[(2S)-2-(pyrrolidin-1- 573.2 — ylmethyl)pyrrolidin-1-yl]carbonyl}benzyl)benzenesulfonamide 612 1-[4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 533.0 — yl]amino}methyl)benzoyl]-L-prolinamide 613 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 618.0 — yl]amino}methyl)-N,N-bis(pyridin-3-ylmethyl)benzamide 614 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3-yl] 548.0 — amino}methyl)-N-[(1R,2S)-2-(hydroxymethyl)cyclohexyl]benzamide 615 N-[(1R,2S)-2-(aminocarbonyl)cyclohexyl]-4-({[(4-chlorophenyl) 561.0 — sulfonyl][(3R)-2-oxoazepan-3-yl]amino}methyl)benzamide 616 3-{[4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 555.0 — yl]amino}methyl)benzoyl]amino}benzamide 617 4-({[(4-chlorophenyl)sulfonyl][(3R)-2- 652.0 — oxoazepan-3-yl]amino}methyl)-N-(3-iodobenzyl)benzamide 618 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 530.0 — yl]amino}methyl)-N-(2-furylmethyl)-N-methylbenzamide 619 N-(1-benzylpyrrolidin-3-yl)-4-({[(4-chlorophenyl)sulfonyl][(3R)- 623.0 — 2-oxoazepan-3-yl]amino}methyl)-N-ethylbenzamide 620 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 562.0 — yl]amino}methyl)-N-cyclohexyl-N-(2-hydroxyethyl)benzamide 621 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3-yl]amino} 560.0 — methyl)-N-[(5-hydroxy-4-oxo-4H-pyran-2-yl)methyl]benzamide 622 N-{[3-(4-chlorophenyl)isoxazol-5-yl]methyl}-4-({[(4-chlorophenyl) 627.0 — sulfonyl][(3R)-2-oxoazepan-3-yl]amino}methyl)benzamide 623 N-(4-chloro-2-methylbenzyl)-4-({[(4-chlorophenyl) — 596.0 sulfonyl][(3R)-2-oxoazepan-3-yl]amino}methyl)benzamide 624 N-[(1R,2R)-2-(benzyloxy)cyclopentyl]-4-({[(4-chlorophenyl) 610.0 — sulfonyl][(3R)-2-oxoazepan-3-yl]amino}methyl)benzamide 625 N-[(1R,2R)-2-(benzyloxy)cyclohexyl]-4-({[(4-chlorophenyl) 624.2 — sulfonyl][(3R)-2-oxoazepan-3-yl]amino}methyl)benzamide 626 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3-yl] 583.0 — amino}methyl)-N-isopropyl-N-(2-pyridin-4-ylethyl)benzamide 627 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 518.0 — yl]amino}methyl)-N-(2,2,2-trifluoroethyl)benzamide 628 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3-yl] 543.0 — amino}methyl)-N-[(1,5-dimethyl-1H-pyrrol-2-yl)methyl]benzamide 629 N-benzyl-4-({[(4-chlorophenyl)sulfonyl][(3R)-2- 540.0 — oxoazepan-3-yl]amino}methyl)-N-methylbenzamide 630 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 524.0 — yl]amino}methyl)-N-(2,3-dihydroxypropyl)-N-methylbenzamide 631 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 494.0 — yl]amino}methyl)-N-(2-hydroxyethyl)-N-methylbenzamide 632 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3-yl] 584.0 — amino}methyl)-N-(3-hydroxy-3-phenylpropyl)-N-methylbenzamide 633 4-chloro-N-[4-(morpholin-4-ylcarbonyl)benzyl]-N- 506.0 — [(3R)-2-oxoazepan-3-yl]benzenesulfonamide 634 4-chloro-N-{4-[(3-hydroxypyrrolidin-1-yl)carbonyl]benzyl}- 506.0 — N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 635 N,N-diallyl-4-({[(4-chlorophenyl)sulfonyl][(3R)-2- 516.0 — oxoazepan-3-yl]amino}methyl)benzamide 636 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 541.0 — yl]amino}methyl)-N-(1-pyridin-3-ylethyl)benzamide 637 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 488.0 — yl]amino}methyl)-N-methyl-N-prop-2-yn-1-ylbenzamide 638 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 536.0 — yl]amino}methyl)-N-(2-methoxyethyl)-N-propylbenzamide 639 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 492.0 — yl]amino}methyl)-N-methyl-N-propylbenzamide 640 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 492.0 — yl]amino}methyl)-N-isopropyl-N-methylbenzamide 641 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 536.0 — yl]amino}methyl)-N-(1,4-dioxan-2-ylmethyl)benzamide 642 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 541.0 — yl]amino}methyl)-N-[(3-methylpyridin-2-yl)methyl]benzamide 643 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3-yl] 547.0 — amino}methyl)-N-{[(2R)-1-ethylpyrrolidin-2-yl]methyl}benzamide 644 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3-yl] 533.0 — amino}methyl)-N-methyl-N-(1-methylpyrrolidin-3-yl)benzamide 645 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 546.0 — yl]amino}methyl)-N-[(3-methyl-2-thienyl)methyl]benzamide 646 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3-yl]amino} 558.0 — methyl)-N-[(1,3,5-trimethyl-1H-pyrazol-4-yl)methyl]benzamide 647 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 544.0 — yl]amino}methyl)-N-[(2,5-dimethyl-3-furyl)methyl]benzamide 648 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 516.0 — yl]amino}methyl)-N-(3-furylmethyl)benzamide 649 4-chloro-N-(4-fluoro-3-nitrobenzyl)-N- 456.0 — [(3R)-2-oxoazepan-3-yl]benzenesulfonamide 650 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3-yl] 618.0 — amino}methyl)-N-{1-[4-(methylsulfonyl)phenyl]ethyl}benzamide 651 4-({[(4-chlorophenyl)sulfonyl][(3R)-2-oxoazepan-3- 558.0 — yl]amino}methyl)-N-[1-(4-fluorophenyl)ethyl]benzamide 652 4-chloro-N-(4-cyanobenzyl)-N-[(3R)-2-oxoazepan-3- 418.0 — yl]benzenesulfonamide 653 4-chloro-N-[4-(chloromethyl)benzyl]-N- 441.0 — [(3R)-2-oxoazepan-3-yl]benzenesulfonamide 654 4-chloro-N-[(3R)-2-oxoazepan-3-yl]-N-{4-[(2- 566.0 — phenylpyrrolidin-1-yl)carbonyl]benzyl)benzenesulfonamide 655 4-chloro-N-[4-(2,3-dihydro-1H-indol-1-ylcarbonyl)benzyl]-N- 538.0 — [(3R)-2-oxoazepan-3-yl]benzenesulfonamide 656 4-chloro-N-{4-[(2-methylpyrrolidin-1-yl)carbonyl]benzyl}- 504.0 — N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide 657 4-chloro-N-{4-[(2-ethylpyrrolidin-1-yl)carbonyl]benzyl}- 518.0 — N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide

The following compounds are prepared essentially according to the methods and procedures described above.

Cmpnd. No. Name M + H M + Na 658 4-chloro-N-[(1-isopropyl-1H-1,2,3- 476 — benzotriazol-5-yl)methyl]-N-[(3R)-2- oxoazepan-3-yl]benzenesulfonamide 659 4-chloro-N-(1,3-dihydro-2,1,3- 451 — benzothiadiazol-5-ylmethyl)-N-[(3R)-2- oxoazepan-3-yl]benzenesulfonamide

The following compounds are prepared essentially according to the methods and procedures described above.

Cmpnd No. Name M + H M + Na 660

4-Chloro-N-[4-(2,3-dihydro-indole-1-carbonyl)-benzyl]-N- [(3R)-2-oxo-azepan-3-yl]-benzenesulfonamide 538.0 — 661 4-Chloro-N-[4-(2-methyl-pyrrolidine-1-carbonyl)-benzyl]-N-[(3R)-2- 504.0 — oxo-azepan-3-yl]-benzenesulfonamide 662 4-Chloro-N-[4-(2-ethyl-pyrrolidine-1-carbonyl)-benzyl]-N-[(3R)-2-oxo- 518.0 — azepan-3-yl]-benzenesulfonamide 663 4-Chloro-N-[(3R)-2-oxo-azepan-3-yl]-N-[4-(1H-tetrazol-5-yl)- 461.0 — benzyl]-benzenesulfonamide 664 4-Chloro-N-[(3R)-2-oxo-azepan-3-yl]-N-[4-(3-pyridin-2-yl-[1,2,4]oxadiazol- 538.0 — 5-yl)-benzyl]-benzenesulfonamide 665 4-Chloro-N-[(3R)-2-oxo-azepan-3-yl]-N-[4-(3-pyridin-4-yl-[1,2,4]oxadiazol- 538.0 — 5-yl)-benzyl]-benzenesulfonamide 666

4-Chloro-N-[(3R)-2-oxo-azepan-3-yl]-N-{4-[3-(4-trifluoromethyl-phenyl)- [1,2,4]oxadiazol-5-yl]-benzyl}-benzenesulfonamide 605.0 — 667 4-Chloro-N-[(3R)-2-oxo-azepan-3-yl]-N-[4-(3-p-tolyl-[1,2,4]oxadiazol-5- 551.0 — yl)-benzyl]-benzenesulfonamide 668 4-Chloro-N-{4-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-benzyl}-N- 555.0 — [(3R)-2-oxo-azepan-3-yl]-benzenesulfonamide 669 4-Chloro-N-[(3R)-2-oxo-azepan-3-yl]-N-[4-(3-phenyl-[1,2,4]oxadiazol-5- 537.0 — yl)-benzyl]-benzenesulfonamide 670 4-Chloro-N-{4-[5-(3-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-benzyl}-N- 567.0 — [(3R)-2-oxo-azepan-3-yl]-benzenesulfonamide 671 4-Chloro-N-{4-[5-(4-hydroxy-phenyl)-[1,3,4]oxadiazol-2-yl]-benzyl}-N- 553.0 — [(3R)-2-oxo-azepan-3-yl]-benzenesulfonamide 672 4-Chloro-N-[(3R)-2-oxo-azepan-3-yl]-N-[4-(5-phenyl-[1,3,4]oxadiazol-2- 537.0 — yl)-benzyl]-benzenesulfonamide 673 4-Chloro-N-{4-[5-(4-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-benzyl}-N- 567.0 — [(3R)-2-oxo-azepan-3-yl]-benzenesulfonamide 674 4-Chloro-N-{4-[5-(2-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-benzyl}-N- 567.0 — [(3R)-2-oxo-azepan-3-yl]-benzenesulfonamide 675 4-Chloro-N-[(3R)-2-oxo-azepan-3-yl]-N-[4-(5-m-tolyl-[1,3,4]oxadiazol- 551.0 — 2-yl)-benzyl]-benzenesulfonamide 676 N-[4-(5-Benzyl-[1,3,4]oxadiazol-2-yl)-benzyl]-4-chloro-N-[(3R)-2-oxo- 551.0 — azepan-3-yl]-benzenesulfonamide 677 4-Chloro-N-[(3R)-2-oxo-azepan-3-yl]-N-[4-(5-pyridin-4-yl-[1,3,4]oxadiazol- 538.0 — 2-yl)-benzyl]-benzenesulfonamide 678 4-Chloro-N-[4-(5-furan-2-yl-[1,3,4]oxadiazol-2-yl)-benzyl]-N-[(3R)-2- 527.0 — oxo-azepan-3-yl]-benzenesulfonamide 679 4-Chloro-N-{4-[5-(2,5-dichloro-phenyl)-[1,3,4]oxadiazol-2-yl]-benzyl}-N- 606.0 — [(3R)-2-oxo-azepan-3-yl]-benzenesulfonamide 680 4-Chloro-N-{4-[5-(4-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-benzyl}-N- 571.0 — [(3R)-2-oxo-azepan-3-yl]-benzenesulfonamide 681 4-Chloro-N-[(3R)-2-oxo-azepan-3-yl]-N-[4-(5-pyridin-3-yl-[1,3,4]oxadiazol- 538.0 — 2-yl)-benzyl]-benzenesulfonamide 682 4-Chloro-N-[(3R)-2-oxo-azepan-3-yl]-N-[4-(5-propyl-[1,3,4]oxadiazol- 503.0 — 2-yl)-benzyl]-benzenesulfonamide 683 4-Chloro-N-{4-[5-(3-methyl-3H-imidazol-4-yl)-[1,3,4]oxadiazol-2-yl]- 541.0 — benzyl}-N-[(3R)-2-oxo-azepan-3-yl]-benzenesulfonamide 684 4-Chloro-N-[4-(5-methoxymethyl-[1,3,4]oxadiazol-2-yl)-benzyl]-N-[(3R)- 505.0 — 2-oxo-azepan-3-yl]-benzenesulfonamide 685 N-[4-(5-Butyl-[1,3,4]oxadiazol-2-yl)-benzyl]-4-chloro-N-[(3R)-2-oxo- 517.0 — azepan-3-yl]-benzenesulfonamide 686 4-Chloro-N-{4-[5-(5-methyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-benzyl}- 557.0 — N-[(3R)-2-oxo-azepan-3-yl]-benzenesulfonamide 687 4-Chloro-N-[4-(5-isopropyl-[1,3,4]oxadiazol-2-yl)-benzyl]-N-[(3R)-2- 503.0 — oxo-azepan-3-yl]-benzenesulfonamide 688 4-Chloro-N-[(3R)-2-oxo-azepan-3-yl]-N-[4-(5-thiophen-3-yl-[1,3,4]oxadiazol- 543.0 — 2-yl)-benzyl]-benzenesulfonamide 689 N-[4-(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-benzyl]-4-chloro-N-[(3R)-2-oxo- 517.0 — azepan-3-yl]-benzenesulfonamide 690 4-Chloro-N-[4-(5-cyclohexyl-[1,3,4]oxadiazol-2-yl)-benzyl]-N-[(3R)-2- 543.0 — oxo-azepan-3-yl]-benzenesulfonamide

Notch Signaling Assay for Selective Inhibitors of Gamma Secretase.

A convergence of evidence indicates that the gamma secretase complex, comprised of the presenilin subunits, mediates the intra-membrane cleavage of Amyloid precursor protein (APP), and the Notch family of proteins (De Strooper, B., P. Saftig, K. Craessaerts, H. Vanderstichele, G. Guhde, W. Annaert, K. Von Figura and F. Van Leuven (1998). “Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein.” Nature 391(6665): 387-90; De Strooper, B., W. Annaert, P. Cupers, P. Saftig, K. Craessaerts, J. S. Mumm, E. H. Schroeter, V. Schrijvers, M. S. Wolfe, W. J. Ray et al. (1999). “A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain.” Nature 398(6727): 518-22; Mumm, J. S., E. H. Schroeter, M. T. Saxena, A. Griesemer, X. Tian, D. J. Pan, W. J. Ray and R. Kopan (2000). “A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1.” Mol Cell 5(2): 197-206; Zhang, Z., P. Nadeau, W. Song, D. Donoviel, M. Yuan, A. Bernstein and B. A. Yankner (2000). “Presenilins are required for gamma-secretase cleavage of beta-APP and transmembrane cleavage of Notch-1.” Nat Cell Biol 2(7): 463-5). Cleavage of APP by gamma secretase leads to β-amyloid synthesis. Cleavage of Notch1 by gamma secretase results in release of the Notch intracellular domain (NICD), which translocates to the nucleus and activates gene expression (Jarriault, S., C. Brou, F. Logeat, E. H. Schroeter, R. Kopan and A. Israel (1995). “Signalling downstream of activated mammalian Notch.” Nature 377(6547): 355-8; Kopan, R., E. H. Schroeter, H. Weintraub and J. S. Nye (1996). “Signal transduction by activated Notch: importance of proteolytic processing and its regulation by the extracellular domain.” Proc Natl Acad Sci USA 93(4): 1683-8; Schroeter, E. H., J. A. Kisslinger and R. Kopan (1998). “Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain.” Nature 393(6683): 382-6). In particular, Notch signaling activates transcription of the mammalian homolog of the Drosophila transcription factor hairy-enhancer of split (Hes). Transcriptional activation of Hes1 is mediated by de-repression of CBF1/RBPJk upon binding by NICD in the nucleus. These facts have been exploited to develop a reporter gene assay for Notch Signaling Hsieh, J. J., T. Henkel, P. Salmon, E. Robey, M. G. Peterson and S. D. Hayward (1996). “Truncated mammalian Notch1 activates CBF1/RBPJk-repressed genes by a mechanism resembling that of Epstein-Barr virus EBNA2.” Mol Cell Biol 16(3): 952-9; Lu, F. M. and S. E. Lux (1996). “Constitutively active human Notch1 binds to the transcription factor CBF1 and stimulates transcription through a promoter containing a CBF1-responsive element.” Proc Natl Acad Sci USA 93(11): 5663-7).

Gamma secretase inhibitors have been observed to block NICD formation, and inhibit Notch signaling (De Strooper, B., W. Annaert, P. Cupers, P. Saftig, K. Craessaerts, J. S. Mumm, E. H. Schroeter, V. Schrijvers, M. S. Wolfe, W. J. Ray et al. (1999). “A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain.” Nature 398(6727): 518-22). Due to the importance of Notch signaling in cell fate determination, and tissue differentiation during both development and in the adult, inhibition of Notch signaling by gamma secretase inhibitors is postulated to be a limiting factor in their therapeutic utility. In order to identify selective gamma secretase inhibitors, testing herein employs a reporter gene based Notch signaling assay using a constitutively active rat Notch1 construct (ZEDN1) provided by Dr. Gerry Weinmaster, [University of California at Los Angeles (UCLA)] as described by Shawber, et al., Development 122(12): 3765-73, (1996). “Notch signaling inhibits muscle cell differentiation through a CBF1-independent pathway.” Development 122(12): 3765-73 in combination with the CBF1 repressible Luciferase reporter gene 4xwtCBF1Luc (Hsieh, J. J., et al., (1996). Mol Cell Biol 16(3): 952-9).

When 4xwtCBF1 Luciferase is co-transfected with NotchΔE (ZEDN1), γ-secretase cleavage of NotchΔE releases the Notch intracellular domain (NICD), which translocates to the nucleus and de-represses CBF1mediated transcriptional repression, leading to transcription of the Luciferase reporter gene. Luciferase activity is easily assayed in cell extracts using commercially available kits. The activity of the reporter gene is directly correlated with gamma secretase cleavage of NotchΔE, and as such, a reduction in Luciferase activity provides a convenient measure of inhibition of gamma secretase cleavage of NotchΔE. A comparison of the IC50 values of compounds for inhibition of Notch signaling versus inhibition of β-amyloid production in 293sw cells is employed to guide in the selection of compounds that have the desired property of potent inhibition of β-amyloid synthesis with minimal inhibition of Notch Signaling.

Compounds of the invention are active in the above assay. Representative compounds are: compounds 77, 157, 249, 269, 275, 537, and 593, which exhibit an IC₅₀ within the range of from about 0.1-25 nM; compounds 85, 136, 153, 163, 227, 486, 553, 636, and 663, which exhibit an IC₅₀ within the range of from about 25-100 nM; compounds 52, 66, 108, 145, 160, 505, 579, and 609, which exhibit an IC₅₀ within the range of from about 100-1000 nM; compounds 14, 89, 148, 206, 338, 613, and 672, which exhibit an IC₅₀ of >1000 nM.

The invention and the manner and process of making and using it, are now described in such full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains, to make and use the same. It is to be understood that the foregoing describes preferred embodiments of the invention and that modifications may be made therein without departing from the spirit or scope of the invention as set forth in the claims. To particularly point out and distinctly claim the subject matter regarded as invention, the following claims conclude this specification. 

1. A compound of the formula

or a pharmaceutically acceptable salt thereof wherein n is 1, 2, or 3; R₁ is aryl C₁-C₈ alkyl, aryl C₂-C₆ alkenyl, or arylalkynyl, wherein the aryl group is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, haloalkyl, haloalkoxy, heteroaryl, heteroaryl(C₁-C₆)alkoxy, arylalkoxy, aryloxy, C₁-C₆ alkoxycarbonyl, —O—CH₂CH₂—O—, —O—CH₂—O—, —C(O)NR₃₀R₃₁, —NHR′, —NR′R″, —N(R₁₆)C(O)—R₁₇, heterocycloalkyl, phenyl, aryl C₁-C₆ alkanoyl, phenylalkoxy, phenyloxy, CN, —SO₂-aryl, —S(O)_(x)—R₂₅, —(C₁-C₄ alkyl)-S(O)_(x)—R₂₅, —(C₁-C₄ alkyl)-SO₂-aryl, OH, C₁-C₆ thioalkoxy, C₂-C₆ alkenyl, —O—SO₂-aryl, CO₂H, wherein the heteroaryl portions of the above group are optionally substituted with 1, 2, or 3 groups that are independently C₁-C₆ alkyl, heteroaryl optionally substituted with 1 or 2 groups that are independently halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkoxyalkyl, CN, C₁-C₆ alkoxy, C₁-C₄ alkoxy C₁-C₄ alkyl, C₃-C₆ cycloalkyl, halogen, or phenyl optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, OH, C₁-C₆ alkyl, C₁-C₄ alkoxy, CF₃, OCF₃, CN, or C₁-C₆ thioalkoxy, wherein the heterocycloalkyl and aryl portions of the above substituents are optionally substituted with 1 or 2 groups that are independently heteroaryl optionally substituted with 1 or 2 groups that are independently halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkoxyalkyl, CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₄ alkoxy C₁-C₄ alkyl, C₃-C₆ cycloalkyl, halogen, or phenyl optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, OH, C₁-C₆ alkyl, C₁-C₄ alkoxy, CF₃, OCF₃, CN, or C₁-C₆ thioalkoxy, R₁₆ is H or C₁-C₆ alkyl; R₁₇ is C₁-C₆ alkyl, aryl, heteroaryl, C₁-C₆ alkoxy, OH, aryloxy, heteroaryloxy, aryl(C₁-C₆)alkoxy, —NR₁₈R₁₉, cycloalkyl, or arylalkyl, wherein the cyclic portions of each of the above are optionally substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, alkoxy, halo, haloalkyl, haloalkoxy, CN, NH₂, NH(alkyl), N(alkyl)(alkyl), CO₂H, or C₁-C₆ alkoxycarbonyl; R₁₈ and R₁₉ are independently H, C₁-C₆ alkyl, aryl, heteroaryl, heterocycloalkyl or aryl(C₁-C₆)alkyl, wherein the cyclic portions of each are optionally substituted with 1, 2, or 3 groups that are independently alkyl, alkoxy, halogen, hydroxyl, CF₃, or OCF₃; wherein R′ at each occurrence is independently H, C₁-C₆ alkyl, aryl, aryl(C₁-C₄)alkyl, C₁-C₆ alkanoyl, C₃-C₈ cycloalkyl, aryl(C₁-C₆)alkanoyl, heterocycloalkyl, heteroaryl(C₁-C₄)alkyl, —SO₂-alkyl, —SO₂-aryl, —SO₂-heteroaryl, heterocycloalkyl(C₁-C₆)alkanoyl, or heteroaryl(C₁-C₆)alkanoyl, wherein the alkyl portion of the alkyl and alkanoyl groups are optionally substituted with halogen or C₁-C₆ alkoxy, wherein the aryl, and heteroaryl groups are optionally substituted with alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, wherein R″ at each occurrence is independently H, or C₁-C₆ alkyl, wherein the alkyl group is optionally substituted with halogen, or R₁ is C₃-C₇ cycloalkyl(C₁-C₆ alkyl) wherein the cyclic portion is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, C₁-C₆ alkyl, OH, alkoxycarbonyl, or C₁-C₆ alkoxy; or R₁ is C₁-C₁₄ alkyl, C₂-C₁₆ alkenyl, or C₂-C₈ alkynyl, each of which is optionally substituted with 1 or 2 groups that are independently OH, halogen, C₁-C₆ alkoxy, aryl, arylalkoxy, aryloxy, heteroaryl, heterocycloalkyl, aryl(C₁-C₆)alkyl, —CO₂—(C₁-C₆ alkyl), —NR′R″, C₁-C₆ thioalkoxy, —NH—S(O)_(x)—R₂₅, —N(C₁-C₆ alkyl) —S(O)_(x)—R₂₅, —S(O)_(x)—R₂₅, —C(O)NR₃₀R₃₁, —N(R₁₆)C(O)NR₁₆R₁₇, or —N(R₁₆)C(O)—R₁₇; wherein the above aryl groups are optionally substituted with 1, 2, or 3 groups that are independently OH, C₁-C₆ alkoxy, C₁-C₆ alkyl, or halogen; R₃₀ and R₃₁ are independently H, C₁-C₆ alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, arylalkanoyl, alkenyl, cycloalkyl, alkynyl, cycloalkenyl, pyridyl, imidazolyl, thiazolyl, oxazolyl, or indolyl, wherein the alkyl portions of the above are optionally substituted with 1, 2, or 3 groups that are independently NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆ alkyl), OH, C₁-C₆ thioalkoxy, heterocycloalkyl, aryl, heteroaryl, CN, halogen, or alkoxy optionally substituted with OH or phenyl, wherein the aryl, heteroaryl and heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, OCF₃, OH, halogen, thioalkoxy, phenyl or heteroaryl; or R₃₀, R₃₁, and the nitrogen to which they are attached form a heterocycloalkyl ring containing from 3 to 7 ring members, wherein the cyclic portions of R₃₀ and R₃₁ or the heterocyclic ring formed from R₃₀, R₃₁, and the nitrogen to which they are attached are optionally substituted with 1, 2, or 3 groups that are independently alkyl, alkoxy, halo, OH, thioalkoxy, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆ alkyl), CF₃, OCF₃, phenyl optionally substituted with a halogen, —(C₁-C₄ alkyl)-N(H or C₁-C₄ alkyl)-phenyl, C₁-C₄ hydroxyalkyl, arylalkoxy, arylalkyl, arylalkanoyl, C(O)NH₂, C(O)NH(C₁-C₆ alkyl), C(O)N(C₁-C₆ alkyl)(C₁-C₆ alkyl), heterocycloalkylalkyl, C₁-C₆ alkoxycarbonyl, C₂-C₆ alkanoyl, heteroaryl, or —SO₂—(C₁-C₆ alkyl) x is 0, 1, or 2; R₂₅ is C₁-C₆ alkyl, OH, NR₂₆R₂₇; R₂₆ and R₂₇ are independently H, C₁-C₆ alkyl, phenyl(C₁-C₄ alkyl), aryl, or heteroaryl; or R₂₆, R₂₇ and the nitrogen to which they are attached form a heterocycloalkyl ring; R₁ is heteroaryl(C₁-C₆)alkyl wherein the cyclic portion is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, aryl, arylalkyl, aryloxy, heteroaryl, —SO₂-aryl, —S(O)_(x)—R₂₅, —(C₁-C₄ alkyl)-S(O)_(x)—R₂₅, CN, C₁-C₆ thioalkoxy, C₁-C₆ alkoxycarbonyl, —NR′R″, —C(O)—NR′R″, heterocycloalkyl, wherein the above aryl groups are optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, or CN; wherein the above heteroaryl and heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, CF₃, (C₁-C₄)alkyl, C₁-C₆ thioalkoxy, OH, C₁-C₄ hydroxyalkyl, or C₁-C₄ alkoxy; or R₁ is heterocycloalkyl(C₁-C₆ alkyl) wherein the cyclic portion is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, aryl, arylalkyl, aryloxy, heteroaryl, —SO₂-aryl, —S(O)_(x)—R₂₅, —(C₁-C₄ alkyl)-S(O)_(x)—R₂₅, CN, C₁-C₆ thioalkoxy, C₁-C₆ alkoxycarbonyl, —NR′R″, —C(O)—NR′R″, heterocycloalkyl; R₂ is H, C₁-C₆ alkyl, or phenyl(C₁-C₄)alkyl; R₃ is H, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, CN, R₄ is H, halogen, C₁-C₆ alkyl optionally substituted with —CO₂—(C₁-C₆ alkyl), C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, CN, aryloxy, isocyanato, —SO₂—(C₁-C₆ alkyl), —NHR′, —NR′R″, C₁-C₆ alkanoyl, heteroaryl, aryl, or R₃ and R₄ and the carbons to which they are attached form a heterocycloalkyl ring which is optionally substituted with 1, 2, or 3 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, or C₁-C₄ alkanoyl wherein the alkanoyl group is optionally substituted with up to 3 halogen atoms; R_(3′) is H, —SO₂—NR′R″, halogen, or R₄ and R_(3′) and the carbons to which they are attached form a benzo ring; or R₄ and R_(3′) and the carbons to which they are attached form a 1-oxa-2,3-diazacyclopentyl ring; R₁₀ and R₁₁ are independently H or F; or R₁₀, R₃, and the carbons to which they are attached for a 1,2,5-oxadiazolyl ring; or R₁₀, R₃, and the carbons to which they are attached form a naphthyl ring.
 2. A compound according to claim 1, wherein R₁ is phenyl(C₁-C₈ alkyl), naphthyl (C₁-C₈ alkyl), phenyl(C₂-C₆ alkenyl), or naphthyl(C₂-C₆ alkenyl), wherein the cyclic portion of each is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, CF₃, OCF₃, thiazolyl, oxazolyl, pyrazolyl, thiazolyl(C₁-C₆)alkoxy, pyridyl(C₁-C₆)alkoxy, phenyl(C₁-C₆ alkanoyl) phenyl(C₁-C₄)alkoxy, oxazolyl(C₁-C₄)alkoxy, pyrazolyl(C₁-C₄)alkoxy, phenyloxy, C₁-C₆ alkoxycarbonyl, triazolyl, —O—CH₂CH₂—O—, —O—CH₂—O—, —C(O)NR₃₀R₃₁, —NHR′, —NR′R″, —N(R_(R16))C(O)—R₁₇, morpholinyl, thiomorpholinyl, thiomorpholinyl S,S-dioxide, piperidinyl, pyrrolidinyl, phenyl, CN, —SO₂-phenyl, —S(O)_(x)—R₂₅, —(C₁-C₄ alkyl)-S(O)_(x)—R₂₅, —(C₁-C₄ alkyl)-SO₂-phenyl, OH, C₁-C₆ thioalkoxy, C₂-C₆ alkenyl, —O—SO₂-phenyl, or hydroxyalkyl, wherein the heteroaryl group is optionally substituted with 1, 2, or 3 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, or halogen, wherein the heterocycloalkyl group is optionally substituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, or halogen, wherein the above phenyl groups are optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, C₁-C₆ alkyl, or C₁-C₄ alkoxy, R₁₆ is H or C₁-C₆ alkyl; R₁₇ is C₁-C₆ alkyl, phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, thienyl, oxazolyl, thiazolyl, furanyl, C₁-C₆ alkoxy, OH, phenyloxy, pyridyloxy, pyrimidyloxy, pyridazyloxy, pyrazinyloxy, thienyloxy, oxazolyloxy, thiazolyloxy, furanyloxy, phenyl(C₁-C₆)alkoxy, or —NR₁₈R₁₉; R₁₈ and R₁₉ are independently H, C₁-C₆ alkyl, phenyl, pyridyl, thienyl, furanyl, piperidinyl, pyrrolidinyl, dioxolanyl, dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, tetrahydro-thiopyranyl 1,1-dioxide, or phenyl(C₁-C₆) alkyl; R₁ is C₃-C₇ cycloalkyl(C₁-C₆ alkyl) wherein the cyclic portion is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, C₁-C₆ alkyl, OH, alkoxycarbonyl, or C₁-C₆ alkoxy; or R₁ is C₁-C₁₄ alkyl, C₂-C₁₆ alkenyl, or C₂-C₆ alkynyl, each of which is optionally substituted with 1 or 2 groups that are independently OH, halogen, C₁-C₆ alkoxy, phenyl, naphthyl, pyridyl, phenyl(C₁-C₄)alkoxy, phenyloxy, —CO₂—(C₁-C₆ alkyl), —NR′R″, C₁-C₆ thioalkoxy, CN, —NH—S(O)_(x)—R₂₅, —N(C₁-C₆ alkyl) —S(O)_(x)—R₂₅, —S(O)_(x)—R₂₅, —C(O)NR₃₀R₃₁, —N(R₁₆)C(O)NR₁₆R₁₇, or —N(R₁₆)C(O)—R₁₇; wherein the above cyclic portions of the above groups are optionally substituted with 1, 2, 3, or 4 groups that are independently OH, C₁-C₆ alkoxy, C₁-C₆ alkyl, or halogen; R₂₅ is C₁-C₆ alkyl, OH, NR₂₆R₂₇; R₂₆ and R₂₇ are independently H, C₁-C₆ alkyl, phenyl(C₁-C₄ alkyl), phenyl, naphthyl, or pyridyl, pyrimidyl, pyridazyl, pyrazinyl, thienyl, oxazolyl, thiazolyl, furanyl; or R₂₆, R₂₇ and the nitrogen to which they are attached form a 5, 6, or 7 membered heterocycloalkyl ring; or R₁ is thienyl(C₁-C₆ alkyl), pyridyl(C₁-C₆ alkyl), furanyl(C₁-C₆ alkyl), pyrazolyl(C₁-C₆ alkyl), pyrrolyl(C₁-C₆ alkyl), thiazolyl(C₁-C₆ alkyl), 1,2,3-thiadiazolyl(C₁-C₆ alkyl), 1,2,4-thiadiazolyl(C₁-C₆ alkyl), 1,3,4-oxadiazole(C₁-C₆ alkyl), 1,2,4-oxadiazole(C₁-C₆ alkyl), indolyl(C₁-C₆ alkyl), triazolyl(C₁-C₆ alkyl), imidazolyl(C₁-C₆ alkyl), isoxazolyl(C₁-C₆ alkyl), benzothienyl(C₁-C₆ alkyl), benzofuranyl(C₁-C₆ alkyl), quinolinyl(C₁-C₆ alkyl), imidazo[2,1-b]thiazolyl(C₁-C₆ alkyl), benzo[c][1,2,5]thiadiazolyl(C₁-C₆ alkyl), benzoimidazolyl(C₁-C₆ alkyl), benzooxazolyl(C₁-C₆ alkyl), benzo[1 ,2,5]oxadiazolyl(C₁-C₆ alkyl), 1H-indazolyl(C₁-C₆ alkyl), 1H-benzotriazolyl(C₁-C₆ alkyl), furo[3,2-b]pyridinyl(C₁-C₆ alkyl), 1H-pyrazolo[3,4-b]pyridinyl(C₁-C₆ alkyl), 1H-pyrazolo[3,4-c]pyridinyl(C₁-C₆ alkyl), quinoxalinyl(C₁-C₆ alkyl), or isoquinolinyl(C₁-C₆ alkyl), wherein the cyclic portions of each of the above are optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, phenyl, phenyl(C₁-C₆ alkyl), phenyloxy, pyrazolyl, imidazolyl, furanyl, thienyl, morpholinyl, —SO₂-phenyl, —SO₂—(C₁-C₆ alkyl), —S(O)_(x)—R₂₅, —(C₁-C₄ alkyl)-S(O)_(x)—R₂₅, CN, C₁-C₆ thioalkoxy, C₁-C₆ alkoxycarbonyl, —NR′R″, —C(O)—NR′R″, pyridyl, piperidinyl, piperazinyl, pyrrolidinyl, or tetrahydrofuranyl, wherein the above phenyl groups are optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, or CN; wherein the above heteroaryl and heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, CF₃, (C₁-C₄)alkyl, C₁-C₆ thioalkoxy, or C₁-C₄ alkoxy; R′ is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, phenyl(C₁-C₄)alkyl, C₁-C₆ alkanoyl, phenyl (C₁-C₆)alkanoyl, pyridyl(C₁-C₄)alkyl, pyrimidyl(C₁-C₄)alkyl, pyridazyl(C₁-C₄)alkyl, pyrazinyl(C₁-C₄)alkyl, thienyl(C₁-C₄)alkyl, oxazolyl(C₁-C₄)alkyl, thiazolyl(C₁-C₄)alkyl, furanyl(C₁-C₄)alkyl, piperidinyl(C₁-C₄)alkyl, —SO₂-alkyl, —SO₂-phenyl, —SO₂-pyridyl, —SO₂-pyrimidyl, —SO₂-pyridazyl, —SO₂-pyrazinyl, —SO₂-thienyl, —SO₂-oxazolyl, —SO₂-thiazolyl, —SO₂-furanyl, pyridyl(C₁-C₆)alkanoyl, pyrimidyl(C₁-C₆)alkanoyl, pyridazyl(C₁-C₆)alkanoyl, pyrazinyl(C₁-C₆)alkanoyl, thienyl(C₁-C₆)alkanoyl, oxazolyl(C₁-C₆)alkanoyl, thiazolyl(C₁-C₆)alkanoyl, or furanyl(C₁-C₆)alkanoyl, wherein the alkyl portion of the alkyl and alkanoyl groups are optionally substituted with halogen or C₁-C₆ alkoxy, wherein the aryl, and heteroaryl groups are optionally substituted with alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, R″ is H, or C₁-C₆ alkyl, wherein the alkyl group is optionally substituted with halogen, or R₁ is 4-oxo-4H-chromenyl(C₁-C₆ alkyl), 2H-chromenyl(C₁-C₆ alkyl), pyrrolidinonyl dione(C₁-C₆ alkyl), pyrrolidinonyl (C₁-C₆ alkyl), isoindolyl dione(C₁-C₆ alkyl), 1,3-dioxolanyl(C₁-C₆ alkyl), dioxanyl(C₁-C₆ alkyl), tetrahydropyranyl(C₁-C₆ alkyl), indolinyl(C₁-C₆ alkyl), 3-oxo-1,3-dihydro-benzo[c]isoxazolyl(C₁-C₆ alkyl), 2-oxo-2,3-dihydro-1H-benzoimidazolyl(C₁-C₆ alkyl), 3-oxo-3,4-dihydro-1H-2-oxa-3lambda4-thia-1,4-diaza-naphthyl(C₁-C₆ alkyl), 3,3-dimethyl-3H-indazolyl(C₁-C₆ alkyl), or piperidinyl(C₁-C₆ alkyl), wherein the cyclic portion of each is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, phenyl, phenyl(C₁-C₆ alkyl), phenyloxy, pyrazolyl, imidazolyl, furanyl, thienyl, morpholinyl, —SO₂-phenyl, —SO₂—(C₁-C₆ alkyl), —S(O)_(x)—R₂₅, —(C₁-C₄ alkyl)-S(O)_(x)—R₂₅, CN, C₁-C₆ thioalkoxy, C₁-C₆ alkoxycarbonyl, —NR′R″, —C(O)—NR′R″, pyridyl, piperidinyl, piperazinyl, pyrrolidinyl, or tetrahydrofuranyl, wherein the above phenyl groups are optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, or CN; wherein the above heteroaryl and heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, CF₃, (C₁-C₄)alkyl, C₁-C₆ thioalkoxy, or C₁-C₄ alkoxy; R₂ is H, C₁-C₄ alkyl, or benzyl; R₃ is H, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, CF₃, CN, R₄ is H, halogen, C₁-C₆ alkyl optionally substituted with —CO₂—(C₁-C₆ alkyl), C₁-C₆ alkoxy, C₁-C₆ haloalkyl, OCF₃, CN, phenyloxy, isocyanato, —SO₂—(C₁-C₆ alkyl), —NHR′, —NR′R″, C₁-C₆ alkanoyl, oxazolyl, pyrazolyl, thiazolyl, pyridyl, furanyl or thienyl, phenyl, or R₃ and R₄ and the carbons to which they are attached form a piperidinyl or pyrrolidinyl ring which is optionally substituted with 1, 2, or 3 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, or C₁-C₄ alkanoyl wherein the alkanoyl group is optionally substituted with up to 3 halogen atoms; R_(3′) is H, —SO₂—NR′R″, or halogen; or R₄ and R_(3′) and the carbons to which they are attached form a benzo ring.
 3. A compound according to claim 2, of the formula:

wherein alk is

wherein m is C, 1, 2, 3, 4, 5, or 6; R₂₀ is H or methyl; and the alky group is optionally substituted with phenyl; R₅ is H, C₁-C₆ alkoxy, CF₃, morpholinyl, oxazolyl, pyrazolyl, thiomorpholinyl, thiomorpholinyl S,S-dioxide, piperidinyl, pyrrolidinyl, halogen, C₁-C₆ alkyl, phenyl optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, C₁-C₆ alkyl, or C₁-C₄ alkoxy, morpholin-4-yl, phenyl, —O—(CH₂)—C(O)O—(CH₂CH₃), CN, —(C₁-C₄ alkyl)-SO₂-phenyl, R₆ is H, C₁-C₆ alkoxy, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, CF₃, OCF₃, phenyl(C₁-C₄)alkoxy, phenyloxy, C₁-C₆ alkoxycarbonyl, CN, C₂-C₆ alkenyl, wherein the above phenyl groups are optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₄ alkoxy, C₁-C₄ alkoxycarbonyl, or benzyloxy; or R₅, R₆, and the carbons to which they are attached form a benzo ring, which is optionally substituted with 1 or 2 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃; R₇ is H, OH, C₁-C₆ alkoxy, CO₂H, haloalkyl, CN, triazolyl, tetrazolyl, NO₂, phenyl(C₁-C₆ alkanoyl),

—O—SO₂-phenyl, —S(O)_(x)—R₂₅, —(C₁-C₄ alkyl)-S(O)_(x)—R₂₅, halogen, C₁-C₆ alkyl, phenyloxy, CF₃, C₁-C₆ alkoxycarbonyl, —(C₁-C₄ alkyl)-C(O)NR₃₀R₃₁, —O—(C₁-C₄ alkyl)-C(O)NR₃₀R₃₁, —NHR′, —NR′R″, pyridyl, oxazolyl, oxadiazolyl, —N(R₁₆)C(O)—R₁₇, thiazolyl(C₁-C₆)alkoxy, pyridyl(C₁-C₆)alkoxy, oxazolyl(C₁-C₄)alkoxy, or pyrazolyl(C₁-C₄)alkoxy, wherein the cyclic portions of the above are optionally substituted with 1, 2, or 3 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₄ alkoxy C₁-C₄ alkyl, pyridyl, pyrrolyl, imidazolyl, furanyl, thienyl optionally substituted with 1 or 2 methyls, halogen, C₃-C₆ cycloalkyl (in one aspect, cyclohexyl) or phenyl optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, OH, C₁-C₆ alkyl, C₁-C₄ alkoxy, CF₃, OCF₃, CN, or C₁-C₆ thioalkoxy, or R₇ is methoxycarbonyl, methoxy, ethoxy, isopropoxy, ethoxy substituted with thiazol-5-yl, wherein the thiazolyl ring is substituted with methyl, —SCH₃, methyl, isopropyl, tert-butyl, isobutyl, F, Br, Cl, CF₃, OCF₃, cyano, N(CH₃)₂, N(C₂ alkyl substituted with Cl)(C₂ alkyl substituted with Cl), phenyl, phenyl substituted with methyl, benzyloxy, NO₂, —S(O)—C₁-C₆ alkyl, —SO₂—C₁-C₆ alkyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆ alkyl), —N(R₁₆)C(O)R₁₇, —C(O)NR₃₀R₃₁, C₁-C₂ haloalkyl, phenyloxy, —O—SO₂-(4-chlorophenyl), —NH—C(O)—CH₃, —O—C(O)—CH₃, thiazolyl substituted with tert-butyl, or OH; wherein R₃₀ and R₃₁ are independently H, C₁-C₆ alkyl, phenyl, phenyl C₁-C₆ alkyl, benzyl, phenylalkanoyl, C₂-C₆ alkenyl, C₃-C₆ cycloalkyl, alkynyl, cycloalkenyl, piperidinyl optionally substituted with C₁-C₄ alkyl or C₂-C₆ alkanoyl, pyridyl C₁-C₆ alkyl, pyrazolyl C₁-C₆ alkyl, C₂-C₆ alkynyl, tetrahydronaphthyl, tetrahydrofuranyl, dihydrofuranonyl, cyclohexenyl, pyrrolidinyl, pyrazolyl, naphthyl, quinuclidinyl, 4H-pyranonyl (preferably 3-hydroxy 4H-pyranonyl), 1,4-dioxanyl, tetrahydronaphthyl C₁-C₆ alkyl, tetrahydrofuranyl C₁-C₆ alkyl, cyclohexenyl C₁-C₆ alkyl, pyrrolidinyl C₁-C₆ alkyl, pyrazolyl C₁-C₆ alkyl, naphthyl C₁-C₆ alkyl, quinuclidinyl C₁-C₆ alkyl, 4H-pyranonyl C₁-C₆ alkyl (preferably 3-hydroxy 4H-pyranonyl C₁-C₆ alkyl), pyrazinyl C₁-C₆ alkyl, pyrrolidinyl C₁-C₆ alkyl, furanyl C₁-C₆ alkyl, thienyl C₁-C₆ alkyl, pyrrolyl C₁-C₆ alkyl, 2,5-dihydro-1H-pyrrolyl C₁-C₆ alkyl, thiazolyl C₁-C₆ alkyl, biphenyl C₁-C₆ alkyl, benzothienyl C₁-C₆ alkyl, furanyl C₁-C₆ alkyl, isoxazolyl C₁-C₆ alkyl, 1,4-dioxanyl C₁-C₆ alkyl, pyridyl, imidazolyl, thiazolyl, oxazolyl, or indolyl, wherein the alkyl portions of the above are optionally substituted with 1, 2, or 3 groups that are independently NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆ alkyl), OH, phenyl, C₁-C₆ thioalkoxy, CN, halogen, or alkoxy optionally substituted with OH or phenyl; or R₃₀, R₃₁, and the nitrogen to which they are attached form a heterocycloalkyl ring that is pyrrolidinyl, piperidinyl, morpholinyl, dihydro 1H-indolyl, tetrahydroisoquinolinyl, thiomorpholinyl, thiomorpholinyl,S,S-dioxide, tetrahydroquinolinyl, or piperazinyl, wherein the cyclic portions of R₃₀ and R₃₁ or the heterocyclic ring formed from R₃₀, R₃₁, and the nitrogen to which they are attached are optionally substituted with 1, 2, or 3 groups that are independently alkyl, alkoxy, halo, thioalkoxy, OH, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆ alkyl), CF₃, OCF₃, phenyl, 4-halophenyl, —(C₁-C₄ alkyl)-N(H or C₁-C₄ alkyl)-phenyl, C₁-C₄ hydroxyalkyl, phenylalkoxy, phenylalkyl, phenylalkanoyl, —(C₁-C₄ alkyl)-pyrrolidinyl, C(O)NH₂, C(O)NH(C₁-C₆ alkyl), C(O)N(C₁-C₆ alkyl)(C₁-C₆ alkyl), C₁-C₆ alkoxycarbonyl, C₂-C₆ alkanoyl, pyrazolyl, pyrrolyl, pyridyl, furanyl, morpholinyl, or —SO₂—(C₁-C₆ alkyl); R′ is H, C₁-C₆ alkyl, or C₁-C₆ alkanoyl, wherein the alkyl portion of the alkyl and alkanoyl groups are optionally substituted with halogen, R″ is H or C₁-C₆ alkyl, wherein the alkyl group is optionally substituted with halogen; R₁₆ is H or C₁-C₆ alkyl; R₁₇ is C₁-C₆ alkyl, phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, thienyl, C₁-C₆ alkoxy, OH, phenyloxy, pyridyloxy, pyrimidyloxy, pyridazyloxy, pyrazinyloxy, thienyloxy, phenyl(C₁-C₄)alkoxy, phenyl C₁-C₆ alkyl, thienyl C₁-C₆ alkyl, C₃-C₆ cycloalkyl, or phenyl C₁-C₆ alkyl, or —NR₁₈R₁₉, wherein the cyclic portions of each of the above are optionally substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, alkoxy, halo, CF₃, OCF₃, CN, NH₂, NH(alkyl), N(alkyl)(alkyl), CO₂H, or C₁-C₆ alkoxycarbonyl; R₁₈ and R₁₉ are independently H, C₁-C₆ alkyl, phenyl, pyridyl, thienyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, tetrahydro-thiopyranyl 1,1-dioxide, isoxazolyl or phenyl(C₁-C₄) alkyl, wherein the cyclic portions of each are optionally substituted with 1, 2, or 3 groups that are independently alkyl, alkoxy, halogen, hydroxyl, CF₃, or OCF₃; or R₆, R₇, and the carbons to which they are attached form a benzo ring, which is optionally substituted with 1 or 2 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃; R₈ is H, halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, or R₇ and R₈ are —O—CH₂CH₂—O—, or —O—CH₂—O—; R₉ is H, halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, or CN.
 4. A compound according to claim 3, wherein R₂, R₁₀ and R₁₁ are simultaneously H.
 5. A compound according to claim 4, wherein R₃ is H, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or CN, R₄ is halogen, C₁-C₄ alkoxy, C₁-C₄ alkyl, CF₃, OCF₃, CN, —NHR′, —NR′R″, or C₁-C₄ alkanoyl, R_(3′) is H, —SO₂—NR′R″, or halogen; or R₄ and R_(3′) and the carbons to which they are attached form a benzo ring. 6-8. (canceled)
 9. A compound according to claim 2, of the formula

alk is

wherein m is 0, 1, 2, 3, 4, 5, or 6; R₂₀ is H or methyl; heteroaryl is thienyl, pyridyl, furanyl, pyrazolyl, pyrrolyl, thiazolyl, 1,2,3-thiadiazolyl, indolyl, triazolyl, benzothienyl, benzofuranyl, quinolinyl, or imidazo[2,1-b]thiazolyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, C₁-C₆ alkyl, phenyl, phenyl(C₁-C₆ alkyl), phenyloxy, pyrazolyl, imidazolyl, furanyl, thienyl, —SO₂-phenyl, CN, C₁-C₆ thioalkoxy, C₁-C₆ alkoxycarbonyl, —NR′R″, piperidinyl, piperazinyl, pyrrolidinyl, or tetrahydrofuranyl, wherein the above phenyl groups are optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, or CN; wherein the pyrazolyl, imidazolyl, furanyl, and thienyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, CF₃, or (C₁-C₄)alkyl; wherein R′ is H, C₁-C₆ alkyl, or C₁-C₆ alkanoyl, wherein the alkyl portion of the alkyl and alkanoyl groups are optionally substituted with halogen, wherein R″ is H, or C₁-C₆ alkyl, wherein the alkyl group is optionally substituted with halogen.
 10. A compound according to claim 9, wherein R₂ is H, methyl, or benzyl; and R₁₀ and R₁₁ are simultaneously H.
 11. A compound according to claim 10, wherein R₃ is H, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or CN, R₄ is halogen, C₁-C₄ alkoxy, C₁-C₄ alkyl, CF₃, OCF₃, CN, —NHR′, —NR′R″, or C₁-C₄ alkanoyl, and R_(3′) is H, —SO₂—NR′R″, or halogen; or R₄ and R_(3′) and the carbons to which they are attached form a benzo ring. 12-13. (canceled)
 14. A compound according to claim 2, wherein R₁ is phenyl(C₂-C₆ alkenyl) or naphthyl(C₂-C₆ alkenyl), wherein the cyclic portion of each is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, CF₃, OCF₃, thiazolyl, oxazolyl, pyrazolyl, thiazolyl(C₁-C₆)alkoxy, pyridyl(C₁-C₆)alkoxy, phenyl(C₁-C₄)alkoxy, oxazolyl(C₁-C₄)alkoxy, pyrazolyl(C₁-C₄)alkoxy, phenyloxy, C₁-C₆ alkoxycarbonyl, —O—CH₂CH₂—O—, —O—CH₂—O—, —NHR′, —NR′R″, morpholinyl, thiomorpholinyl, thiomorpholinyl S,S-dioxide, piperidinyl, pyrrolidinyl, phenyl, CN, —SO₂-phenyl, —(C₁-C₄ alkyl)-SO₂-phenyl, OH, C₁-C₆ thioalkoxy, C₂-C₆ alkenyl,or —O—SO₂-phenyl, wherein the heteroaryl group is optionally substituted with 1, 2, or 3 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, or halogen, the heterocycloalkyl group is optionally substituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, or halogen, the above phenyl groups are optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, C₁-C₆ alkyl, or C₁-C₄ alkoxy, R′ is H, C₁-C₆ alkyl, or C₁-C₆ alkanoyl, wherein the alkyl portion of the alkyl and alkanoyl groups are optionally substituted with halogen, or C₁-C₆ alkoxy, R″ is H or C₁-C₆ alkyl, wherein the alkyl group is optionally substituted with halogen. 15-18. (canceled)
 19. A compound according to claim 1, wherein R₂ is H, methyl, or benzyl; R₁₀ and R₁₁ are simultaneously H; R₃ is H, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or CN, R₄ is halogen, C₁-C₄ alkoxy, C₁-C₄ alkyl, CF₃, OCF₃, CN, —NHR′, —NR′R″, or C₁-C₄ alkanoyl, R_(3′) is H, —SO₂—NR′R″, or halogen; or R₄ and R_(3′) and the carbons to which they are attached form a benzo ring.
 20. A compound according to claim 19, wherein R₁ is C₁-C₁₄ alkyl, C₂-C₁₆ alkenyl, or C₂-C₆ alkynyl, each of which is optionally substituted with 1 or 2 groups that are independently OH, halogen, C₁-C₆ alkoxy, phenyl, naphthyl, phenyl(C₁-C₄)alkoxy, phenyloxy, phenyl(C₁-C₄)alkyl, pyridyl, thienyl, —CO₂—(C₁-C₆ alkyl), —NR′R″, C₁-C₆ thioalkoxy, OH, —N(R₁₆)C(O)—R₁₇, —C(O)NR₃₀R₃₁, —NH—S(O)_(x)—R₂₅, —N(C₁-C₆ alkyl) —S(O)_(x)—R₂₅, CN, or —S(O)_(x)—R₂₅, wherein the above phenyl and naphthyl groups are optionally substituted with 1, 2, or 3 groups that are independently OH, C₁-C₆ alkoxy, C₁-C₆ alkyl, or halogen; x is 0, 1, or 2; R₁₆ is H or C₁-C₆ alkyl; R₁₇ is C₁-C₆ alkyl, phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, thienyl, oxazolyl, thiazolyl, furanyl, C₁-C₆ alkoxy, OH, phenyloxy, pyridyloxy, pyrimidyloxy, pyridazyloxy, pyrazinyloxy, thienyloxy, oxazolyloxy, thiazolyloxy, furanyloxy, phenyl(C₁-C₆)alkoxy, or —NR₁₈R₁₉; R₁₈ and R₁₉ are independently H, C₁-C₆ alkyl, phenyl, pyridyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, tetrahydro-thiopyranyl 1,1-dioxide, or phenyl(C₁-C₄) alkyl; R₂₅ is C₁-C₆ alkyl, OH, NR₂₆R₂₇; R₂₆ and R₂₇ are independently H, C₁-C₆ alkyl, phenyl(C₁-C₄ alkyl), phenyl, naphthyl or pyridyl, pyrimidyl, thienyl, furanyl or quinolinyl; or R₂₆, R₂₇ and the nitrogen to which they are attached form a heterocycloalkyl ring, which contains 2 to 7 carbon atoms, and R₃₀ and R₃₁ are independently H, C₁-C₆ alkyl, phenyl, benzyl, pyridyl, thiazolyl, oxazolyl, or indolyl, or R₃₀, R₃₁, and the nitrogen to which they are attached form a azepanyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, or thiomorpholinyl 1,1-dioxide.
 21. A compound according to claim 19, wherein R₁ is C₃-C₇ cycloalkyl(C₁-C₄ alkyl) wherein the cyclic portion is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxycarbonyl, CO₂H, or C₁-C₆ alkoxy.
 22. A compound according to claim 19, wherein R₁ is 4-oxo-4H-chromen-3-yl(C₁-C₄ alkyl), 2H-chromen-3-yl(C₁-C₄ alkyl), pyrrolidinonyl dione(C₁-C₄ alkyl), isoindol-2-yl dione(C₁-C₄ alkyl), 1,3-dioxolan-2-yl(C₁-C₄ alkyl), dioxanyl(C₁-C₄ alkyl), or tetrahydropyran-2-yl(C₁-C₄ alkyl), wherein the cyclic portion of each is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, or halogen; and R₂ is H.
 23. A pharmaceutical composition comprising a compound or salt of claim 1 and at least one pharmaceutically acceptable carrier, solvent, adjuvant or excipient, or a combination thereof.
 24. A method of treating a patient who has, or in preventing a patient from getting, a disease or condition selected from the group consisting of Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating patients with mild cognitive impairment (MCI) and preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating Down's syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, age related macular degeneration or diffuse Lewy body type of Alzheimer's disease and who is in need of such treatment which comprises administration of a therapeutically effective amount of a compound of claim
 1. 25. (canceled) 